Antidiabetic agents based on aryl and heteroarylacetic acids

ABSTRACT

The instant invention is concerned with aryl and heteroaryl acetic acid and oxyacetic acid compounds, which are useful as antidiabetic compounds. Compositions and methods for their use in the treatment of diabetes and related diseases and for lowering triglyceride levels are disclosed.

This is a division of application Ser. No. 09/331,512, filed Jun. 22,1999, now U.S. Pat. No. 6,160,000, which was filed under 35 USC §371 asthe national stage filing of PCT International Application No.PCT/US97/23646, filed Dec. 19, 1997, and claims priority from U.S.Provisional Application No. 60/034,432, filed Dec. 23, 1996, and No.60/060,113, filed Sep. 26, 1997.

BACKGROUND OF THE INVENTION

Diabetes refers to a disease process derived from multiple causativefactors and characterized by elevated levels of plasma glucose orhyperglycemia. Uncontrolled hyperglycemia is associated with increasedand premature mortality due to an increased risk for microvascular andmacrovascular disease, including nephropathy, neuropathy, retinopathy,hypertension, stroke, and heart disease. Therefore, glucose homeostasisis critically important for the treatment of diabetes.

Type I diabetes (IDDM) is associated with a deficiency of insulin. TypeII, noninsulin dependent diabetes mellitus (NIDDM) is associated with aresistance to the stimulating or regulatory effect of insulin on glucoseand lipid metabolism in the main insulin-sensitive tissues, namely, themuscle, liver and adipose tissue. This resistance to to the effect ofinsulin results in insufficient activation of glucose uptake, oxidationand storage in muscle, inadequate repression of lipolysis in adiposetissue and inadequate supression of glucose production and secretion inliver.

Standard treatments for NIDDM, which have not changed substantially inyears, are all associated with limitations. Physical exercise andreduction in calorie intake improves the diabetic condition; howevercompliance is generally poor. Increasing the plasma level of insulin,either by administering an oral hypoglycemic such as a sulfonylurea(e.g. tolbutamide or glipizide) or by injecting insulin results ininsulin levels which are sufficient to stimulate insulin-resistanttissues. However, low levels of plasma glucose and a heightened level ofinsulin resistance can result.

Thiazolidinediones (glitazones) were suggested to ameliorate manysymptoms of NIDDM. These agents increase insulin sensitivity in muscle,liver and adipose tissue in several animal models of NIDDM, hopefullyresulting in normalized levels of plasma glucose, triglycerides andnonesterified free fatty acids. However, serious undesirable effectshave been observed, including cardiac hypertrophy, hemodilution andliver toxicity.

Hyperlipidemia is a condition that is characterized by an abnormallyhigh level of serum lipids. This includes cholesterol, triglycerides andphospholipids. These lipids do not circulate freely in solution inplasma, but are bound to proteins and transported as macromolecularcomplexes called lipoproteins. See the Merck Manual, 16th Ed. 1992 (seefor example pp. 1039-1040) and “Structure and Metabolism of PlasmaLipoproteins” in Metabolic Basis of Inherited Disease, 6th Ed. 1989, pp.1129-1138. One form of hyperlipidemia is hypercholesterolemia, which ischaracterized by elevated LDL cholesterol levels. The initial treatmentfor hypercholesterolemia is often reduced dietary fat and cholesterol.Coupled with an appropriate exercise regimen, this can be an effectivemeans by which to reduce hyperlipidemia. More typically, this means oflowering hyperlipidemia is insufficient, making drug therapy to reduceserum LDL-cholesterol more appropriate.

Although it is desirable to lower elevated levels of LDL cholesterol, itis also desirable to increase levels of HDL cholesterol, since increasedlevels of HDL are associated with a reduced risk for coronary heartdisease (CHD). See, for example, Gordon, et al., Am. J. Med., 62,707-714 (1977); Stampfer, et al., N. England J. Med., 325, 373-381(1991); and Kannel, et al., Ann. Internal Med., 90, 85-91 (1979). Anexample of an HDL raising agent is nicotinic acid.

It is suggested that thiazolidinedione compounds exert their effects bybinding to the peroxisome proliferator activated receptor (PPAR) familyof receptors, controlling certain transcription elements having to dowith the biological entities listed above. See Hulin et al., CurrentPharm. Design (1996) 2, 85-102. Three sub-types of PPARs have beendiscovered and described: PPARα, PPARγ and PPARδ. PPARα is activated bya number of medium and long-chain fatty acids. It is involved instimulating β-oxidation of fatty acids. PPARα is also activated bycompounds known as fibric acid derivatives. These fibric acidderivatives, such as clofibrate, fenofibrate, bezafibrate, ciprofibrate,beclofibrate and etofibrate, as well as gemfibrozil reduce plasmatriglycerides along with LDL cholesterol, and they are primarily usedfor the treatment of hypertriglyceridemia.

PPARγ receptor subtypes are involved in adipocyte differentiation. TheDNA sequences for the PPARγ receptors are described in Elbrecht, et al.,BBRC 224;431-437 (1996). Although peroxisome proliferators, includingthe fibrates and fatty acids, activate the transcriptional activity ofPPARs, only prostaglandin J₂ derivatives have been identified as naturalligands of the PPARγ subtype, which also binds to thiazolidinedioneantidiabetic agents with high affinity. The glitazones have been shownto bind to the PPARγ subtype.

The human nuclear receptor gene PPARδ (hPPARδ) has been cloned from ahuman osteosarcoma cell cDNA library and is fully described in A.Schmidt et al., Molecular Endocrinology, 6 :1634-1641 (1992), hereinincorporated by reference. PPARδ is also referred as PPARβ and NUC1.

SUMMARY OF THE INVENTION

The present invention is directed to a compound represented by formula Ior Ia:

or a pharmaceutically acceptable salt thereof, wherein:

A is optionally a single or double bonded carbon or a single or doublebond;

R¹ is selected from a group consisting of: H, C₁₋₅ alkyl, C₂₋₁₅ alkenyl,C₂₋₁₅ alkynyl and C₃₋₁₀ cycloalkyl, said alkyl, alkenyl, alkynyl, andcycloalkyl optionally substituted with 1 to 3 groups of R^(a);

R² is selected from a group consisting of: H, C₁₋₁₅ alkyl, C₂₋₁₅alkenyl, OR³, CO₂alkyl, COalkyl, OH, —OC(O)R³, C₂₋₁₅ alkynyl, C₅₋₁₀aryl, C₅₋₁₀ heteroaryl, said alkyl, alkenyl, alkynyl, aryl andheteroaryl optionally substituted with 1 to 3 groups of R^(a);

R³ is selected from a group consisting of: H, NHR¹, NHacyl, C₁₋₁₅ alkyl,C₂₋₁₅ alkenyl, C₁₋₁₅ alkoxy, CO₂alkyl, OH, C₂₋₁₅ alkynyl, C₅₋₁₀ aryl,C₅₋₁₀ heteroaryl said alkyl, alkenyl, alkynyl, aryl and heteroaryloptionally substituted with 1 to 3 groups of R^(a);

R⁴ is selected from the group consisting of: R², —D—R⁵ or

R⁵ is selected from the group consisting of: C₅₋₁₀ aryl and C₅₋₁₀heteroaryl, said aryl and heteroaryl optionally substituted with 1 to 3groups of R^(a);

R⁸ is selected from the group consisting of CR⁶R⁷, O, NR⁶, and S(O)_(P);

R⁶and R⁷ are independently selected from the group consisting of H, C₁₋₆alkyl;

B is a 5 or 6 membered heterocycle containing 0 to 2 double bonds, and 0to 3 heteroatoms selected from the group consisting of O, S and N, theheteroatom being substituted at any position on the five or six memberedheterocycle, the heterocycle being optionally unsubstituted orsubstituted with 1 to 3 groups of R^(a);

D is selected from the group consisting of: O, S(O)p and NR¹;

X¹ and X² are independently selected from a group consisting of: H, OH,C₁₋₁₅ alkyl, C₂₋₁₅ alkenyl, C₂₋₁₅ alkynyl, halo, OR³, C₅₋₁₀ aryl, C₅₋₁₀aralkyl, C₅₋₁₀ heteroaryl and C₁₋₁₀ acyl, said alkyl, alkenyl, alkynyl,aryl and heteroaryl optionally substituted with 1 to 3 groups of R^(a);

R^(a) represents a member selected from the group consisting of: halo,aryl, heteroaryl, CF₃, OCF₃, —O—, CN, NO₂, R³, OR³; SR³, S(O)R³, SO₂R³,NR³R³, NR³COR³, NR³CO₂R³, NR³CON(R³)₂, NR³SO₂R³, COR³, CO₂R³, CON(R³)₂,SO₂N(R³)₂, OCON(R³)₂ said aryl and heteroaryl optionally substitutedwith 1 to 3 groups of halo or C1-6 alkyl;

Y is selected from the group consisting of: S(O)_(p), —CH₂—, CO, NR¹, O,SO₂NH, NHSO₂;

Y² is selected from the group consisting of: O, N(C₁₋₁₅) alkyl,N(CO₂)alkyl, N—Oalkyl, N—Oacyl and N—OH, with the proviso that if Y² isO and R³ is CH₃ then n is 2;

Y¹ is selected from the group consisting of: O, NH, S(O)_(p) and C;

Z is selected from the group consisting of: CO₂R³, R³CO₂R³, CONHSO₂Me,CONH₂ and 5-(1H-tetrazole); or

(Z—W)_(t) or (Z—W)_(v) together with X¹ can form a 5 or 6 membered ring,said ring being a carbocycle, aryl or heteroaryl and optionallysubstituted with 1 to 3 groups of R^(a); in the case where (Z—W)_(t) isused v is 0 or 1; in the case where (Z—W)_(v) is used t is 0 or 1;

t and v are independently 0 or 1 such that t+v=1;

n is 2-4 and

p is 0-2.

Also included in the invention is a pharmaceutical composition which iscomprised of a compound of formula I or Ia in combination with apharmaceutically acceptable carrier.

Also included in the invention is a pharmaceutical composition which iscomprised of a compound of formula I or Ia in combination with one ormore known sulfonylureas, biguanides, α-glucosidase inhibitors, otherinsulin secretogogues or insulin.

Also included in the invention is a method for raising high densitylipoprotein (HDL) plasma levels in a mammal in need of such treatmentcomprising administering an effective amount of a compound of formula Ior Ia.

Also included in the invention is a method for preventing, halting,slowing or otherwise treating the progression of atheroscleroticcardiovascular diseases and related conditions and disease events in amammal in need of such treatment comprising administering an effectiveamount of a compound of formula I or Ia.

Also included in the invention is a method for preventing, halting orslowing the progression of atherosclerotic cardiovascular diseases andrelated conditions and disease events in a mammal in need of suchtreatment comprising administering an effective amount of a compound offormula I or Ia in combination with one or more active agents such asantihyperlipidemic agents, HMG-CoA synthase inhibitors, squaleneepoxidase inhibitors and the like.

Also included in the invention is a method of treating or controllingdiabetes and related diseases such as diabetic retinopathy, diabeticnephropathy and the like, which comprises administering to a mammaliandiabetic patient an effective amount of a compound of formula I or Ia.

Also included in the invention is a method of treating or controllingdiabetes and related diseases such as diabetic retinopathy; diabeticnephropathy and the like, which comprises administering a compound offormula I or Ia in combination with one or more known sulfonylureas,biguanides, α-glucosidase inhibitors, other insulin secretogogues orinsulin.

Also included in the present invention is a method of treatingpancreatitis in a mammalian patient in need of such treatment, which iscomprised of administering to said patient an amount of a compound offormula I or Ia which is effective for treating pancreatitis.

DESCRIPTION OF THE INVENTION

The invention is described herein in detail using the terms definedbelow unless otherwise specified.

The term “alkyl” and the alkyl portion of “acyl” refer to a monovalentalkane (hydrocarbon) derived radical containing from 1 to 15 carbonatoms unless otherwise defined. It may be straight, branched or cyclic.Preferred straight or branched alkyl groups include methyl, ethyl,propyl, isopropyl, butyl and t-butyl. Preferred cycloalkyl groupsinclude cyclopentyl and cyclohexyl.

The carbon chain of “acyl” also includes alkenyl and alkynyl groups asdescribed below, with the double or triple bonds being located inappropriate positions within the chain.

Alkyl also includes a straight or branched alkyl group which contains oris interrupted by a cycloalkylene portion. Examples include thefollowing:

wherein: x and y=from 0-10; and w and z=from 0-9.

The alkylene and monovalent alkyl portion(s) of the alkyl group can beattached at any available point of attachment to the cycloalkyleneportion.

When substituted alkyl is present, this refers to a straight, branchedor cyclic alkyl group as defined above, substituted with 1-3 groups asdefined with respect to each variable.

The term “alkenyl” refers to a hydrocarbon radical straight, branched orcyclic containing from 2 to 15 carbon atoms and at least one carbon tocarbon double bond. Preferably one carbon to carbon double bond ispresent, and up to four non-aromatic (non-resonating) carbon-carbondouble bonds may be present. Preferred alkenyl groups include ethenyl,propenyl, butenyl and cyclohexenyl. As described above with respect toalkyl, the straight, branched or cyclic portion of the alkenyl group maycontain double bonds and may be substituted when a substituted alkenylgroup is provided.

The term “alkynyl” refers to a hydrocarbon radical straight, branched orcyclic, containing from 2 to 15 carbon atoms and at least one carbon tocarbon triple bond. Up to three carbon-carbon triple bonds may bepresent. Preferred alkynyl groups include ethynyl, propynyl and butynyl.As described above with respect to alkyl, the straight, branched orcyclic portion of the alkynyl group may contain triple bonds and may besubstituted when a substituted alkynyl group is provided.

The term “alkoxy” refers to those groups of the designated carbon lengthin either a straight or branched configuration attached through anoxygen linkage and if two or more carbon atoms in length, they mayinclude a double or a triple bond. Exemplary of such alkoxy groups aremethoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiarybutoxy, pentoxy, isopentoxy, hexoxy, isohexoxy, allyloxy, propargyloxy,and the like.

The term halo as used herein, represents fluoro, chloro, bromo or iodo.

Aryl refers to aromatic rings e.g., phenyl, substituted phenyl and likegroups as well as rings which are fused, e.g., naphthyl and the like.Aryl thus contains at least one ring having at least 5 atoms, with up totwo such rings being present, containing up to 10 atoms therein, withalternating (resonating) double bonds between adjacent carbon atoms. Thepreferred aryl groups are phenyl and naphthyl. Aryl groups may likewisebe substituted with 0-3 groups selected from R^(a). The preferred arylgroups are phenyl and naphthyl. Aryl groups may likewise be substitutedas defined below. Preferred substituted aryls include phenyl andnaphthyl substituted with zero or three groups of R^(a).

Heteroaryl is a group containing from 5 to 10 atoms, 1-4 of which areheteroatoms, 0-4 of which heteroatoms are N and 0-1 of which are O or S,said heteroaryl group being unsubstituted or substituted with 0-3 R^(a)groups; examples of heteroaryls are pyridyl, quinolyl, purinyl,imidazolyl, imidazopyridyl and pyrimidinyl.

A subset of compounds of the invention is included herein and describedin connection with formula I or Ia:

as well as pharmaceutically acceptable salts thereof, wherein:

A represents a single or double bonded carbon, or a direct single ordouble bond;

Y represents a member selected from the group consisting of: —S(O)_(p)—wherein p is 0, 1 or 2, —CH₂—, —C(O)—, —NR¹—, —O—, —SO₂NH— and —NHSO₂—;

one of t and v is zero and the other is 1;

W is

 and

Z is selected from the group consisting of: CO₂R^(3′), CONHSO₂C₁₋₆alkyl, CONH₂ and 5-(1H-tetrazolyl); or in the alternative,

one of (Z—W)_(t) and (Z—W)_(v) is taken in combination with X¹ torepresent a 5 or 6 membered fused ring, said ring being a carbocycle,aryl or heteroaryl ring, and being optionally substituted with 1 to 3R^(a) groups;

when (Z—W)_(t) is taken in combination with X¹, v is 0 or 1, and when(Z—W)_(v) is taken in combination with X¹, t is 0 or 1;

X¹ and X² are independently selected from a group consisting of: H, OH,C₁₋₁₅ alkyl, C₂₋₁₅ alkenyl, C₂₋₁₅ alkynyl, halo, C₅₋₁₀ aryl, C₅₋₁₀heteroaryl, C₁₋₁₀ acyl, C₁₋₅ alkoxy, C₅₋₁₀ aryloxy, C₂₋₁₅ alkenyloxy,C₂₋₁₅ alkynyloxy, heteroaryloxy, C₁₋₁₀ acyloxy

said alkyl, alkenyl, alkynyl, aryl, acyl and heteroaryl, and the alkyl,alkenyl, alkynyl, aryl acyl and heteroaryl portions of alkoxy, aryloxy,alkenyloxy, alkynyloxy, heteroaryloxy and acyloxy being optionallysubstituted with 1 to 3 R^(a) groups;

n is 2, 3 or 4;

Y¹ represents O, NH, CH₂ or S(O)_(p) wherein p is as defined above;

B represents a 5 or 6 membered fused ring containing 0 to 2 doublebonds, and optionally containing 1 to 3 heteroatoms selected from thegroup consisting of O, S and N, said ring being optionally substitutedwith 1 to 3 R^(a) groups;

R¹ is selected from a group consisting of: H, C₁₋₁₅ alkyl, C₂₋₁₅ alkenyland C₂₋₁₅ alkynyl, said alkyl, alkenyl and alkynyl being optionallysubstituted with 1 to 3 R^(a) groups;

R² is selected from a group consisting of: H, OH, C₁₋₁₅ alkyl, C₂₋₁₅alkenyl, C₂₋₁₅ alkynyl, C₅₋₁₀ aryl, C₅₋₁₀ heteroaryl, —C(O)C₁₋₁₅ alkyl,CO₂C₁₋₆ alkyl, —OC(O)R^(3′), C₁₋₆ alkoxy, C₅₋₁₀ aryloxy, C₂₋₁₅alkenyloxy, C₂₋₁₅ alkynyloxy, heteroaryloxy and C₁₋₁₀ acyloxy,

said alkyl, alkenyl, alkynyl, aryl and heteroaryl, and the alkyl, aryl,alkenyl, alkynyl heteroaryl and acyl portions of alkoxy, aryloxy,alkenyloxy, alkynyloxy, heteroaryloxy and acyloxy being optionallysubstituted with 1 to 3 R^(a) groups;

R³ is selected from a group consisting of: H, OH, NHR¹, NHacyl, C₁₋₁₅alkyl, C₂₋₁₅ alkenyl, C₁₋₁₅ alkoxy, CO₂alkyl, C₂₋₁₅ alkynyl, C₅₋₁₀ aryl,and C₅₋₁₀ heteroaryl said alkyl, alkenyl, alkynyl, aryl and heteroaryloptionally substituted with 1 to 3 R^(a) groups;

each R^(a) independently represents a member selected from the groupconsisting of: R^(3′), halo, CF₃, OCF₃, CN, NO₂, OR^(3′),S(O)_(p)—R^(3′); N(R^(3′))₂, NR^(3′)COR^(3′), NR^(3′)CO₂R^(3′),NR^(3′)CON(R^(3′))₂, NR^(3′)SO₂R^(3′), C(O)R^(3′), CO₂R^(3′),CON(R^(3′))₂, SO₂N(R^(3′))₂, OCON(R^(3′))₂, and when R^(3′) is presentand represents alkyl, alkenyl, alkynyl, aryl or heteroaryl, said alkyl,alkenyl, alkynyl, aryl or heteroaryl group is optionally substitutedwith 1 to 3 halo, hydroxy, C₁₋₃ alkoxy, carboxy or amino groups, and

when at least two R^(a) groups are present, they may also be taken incombination with any intervening atoms to represent a 4-6 membered ring,said ring containing 0-3 heteroatoms selected from O, S(O)_(p) and N,and said ring being optionally interrupted by 1-2 —C(O)— groups, andoptionally substituted with 1-3 halo, hydroxy, C₁₋₆ alkyl or aminogroups;

R^(3′) represents H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl orheteroaryl;

R⁴ represents R², —D—R⁵ or

D is selected from O, S(O)p, NR¹ and CR⁶R⁷;

R⁵ is selected from the group consisting of: C₅₋₁₀ aryl and C₅₋₁₀heteroaryl, said aryl and heteroaryl being optionally substituted with 1to 3 R^(a) groups;

Y² is selected from the group consisting of: O, N(C₁₋₁₅) alkyl,N(CO₂)alkyl, N—Oalkyl, N—Oacyl and N—OH, with the proviso that if Y² isO and R³ is CH₃ then n is 2;

R⁸ is optional and is selected from the group consisting of CR⁶R⁷, O,NR⁶ and S(O)_(p),

and R⁶ and R⁷ are independently selected from H and C₁₋₆ alkyl.

One embodiment of the invention which is particular interest is realizedwhen Y is O and all other variables are as described above.

Another embodiment of the invention is realized when Y is S(O)_(p), p is0-2 and all other variables are described as above.

Still another embodiment of the invention is realized when Y is —CH₂—and all other variables are described as above.

Yet another embodiment of the invention is realized when Y is CO and allother variables are described as above.

A further embodiment of the invention is realized when Y is NH and allother variables are described as above.

Another embodiment of the invention is realized when Y is NHSO₂ or SO₂NHand all other variables are described as above.

Another embodiment of the invention is realized when (Z—W)_(t) or(Z—W)_(v) together with X¹ form a 5 or 6 membered ring, said ring beinga carbocycle, aryl or heteroaryl and optionally substituted with 1 to 3R^(a) groups. In the case where (Z—W)_(t) is used, v is 0 or 1; in thecase where (Z—W)_(v) is used, t is 0 or 1; and all other variables aredescribed as above.

Another embodiment of the novel compounds of the instant invention isrealized when A is a single or double bonded carbon and all othervariables are described as above.

Still another embodiment of the novel compounds of the instant inventionis realized when A is a single or double bond and all other variablesare described as above.

Still another embodiment of the invention is realized when B is a 5 or 6membered heterocycle containing 0 to 2 double bonds, and 1 to 3heteroatoms selected from the group consisting of O, S and N, theheteroatom being present at any position in the five or six memberedring, the heterocycle being unsubstituted or substituted with 1 to 3R^(a) groups, and all other variables are described as above.

Still another embodiment of the novel compounds of the instant inventionis realized when R⁴ is selected from the group consisting of: R², —D—R⁵and

and all other variables are described as above. Preferably R⁴ representsR² or —D—R⁵.

A preferred embodiment of the invention is realized when:

R¹ is H or C₁₋₅ alkyl;

X¹ and X² are independently H or halo;

B is a 5 or 6 membered heterocycle containing 0 to 2 double bonds, and 1to 3 heteroatoms selected from the group consisting of O, S and N, theheteroatom being at any allowable position in the five or six memberedheterocycle, the heterocycle being unsubstituted or substituted with 1to 3 R^(a) groups;

Y is O, NH or S;

Y¹ is O;

W is —CR⁶R⁷—;

R^(a) is a member selected from the group consisting of: halo, aryl,heteroaryl, CF₃, OCF₃, —O—, CN, NO₂, R^(3′), OR^(3′); SR^(3′),S(O)R^(3′), SO₂R^(3′), NR^(3′)COR^(3′), COR^(3′), CON(R^(3′))₂,SO₂N(R^(3′))₂, said aryl and heteroaryl optionally substituted with 1 to3 halo or C1-6 alkyl groups; and

Z is CO₂R^(3′), CONHSO₂Me, CONH₂ or 5-(1H-tetrazolyl). All othervariables are as originally defined.

Another preferred embodiment of the invention is realized when:

R¹ is H or C₁₋₅ alkyl;

R⁴ is R², —D—R⁵ or

X¹ and X² are independently H or halo;

Y is O, NH or S;

Y¹ is O;

W is —CR⁶R⁷—;

R^(a) is a member selected from the group consisting of: halo, aryl,heteroaryl, CF₃, OCF₃, —O—, CN, NO₂, R^(3′), OR^(3′); SR^(3′),S(O)R^(3′), SO₂R^(3′), NR^(3′)COR^(3′), COR^(3′), CON(R^(3′))₂,SO₂N(R^(3′))₂, wherein R^(3′) represents H, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, aryl or heteroaryl, said aryl and heteroaryl optionallysubstituted with 1 to 3 groups of halo or C₁₋₆ alkyl; and

Z is CO₂R^(3′), CONHSO₂Me, CONH₂ or 5-(1H-tetrazolyl).

Still another preferred embodiment of the invention is realized when:

R¹ is C₁₋₁₅ alkyl;

R⁴ is —D—R⁵ or

X² is H, or halo;

Y is O, NH or S;

Y¹ is O;

R^(a) is a member selected from the group consisting of: halo, aryl,heteroaryl, CF₃, OCF₃, —O—, CN, NO₂, R^(3′), OR^(3′); SR^(3′),S(O)R^(3′), SO₂R^(3′), NR^(3′)COR^(3′), COR^(3′), CON(R^(3′))₂,SO₂N(R^(3′))₂, said aryl and heteroaryl optionally substituted with 1 to3 halo or C₁₋₆ alkyl groups;

R^(3′) represents H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl orheteroaryl, said aryl and heteroaryl optionally substituted with 1 to 3halo or C₁₋₆ alkyl groups;

(Z—W)_(t) or (Z—W)_(v) together with X¹ forms a 5 or 6 membered ring,said ring being a carbocycle, aryl or heteroaryl and optionallysubstituted with 1 to 3 R^(a) groups; in the case where (Z—W)_(t) isused v is 0 or 1; in the case where (Z—W)_(v) is used t is 0 or 1; andall other variables are described as above.

Examples of compounds of the invention include the following:

2-(2-(3-Phenyl-7-propylbenzofuran-6-yloxy)ethyl)-indole-5-acetic acid;

2-(2-(3-(2,2-Dimethylpropyl)-7-propylbenz[4,5]isoxazol-6-yloxy)ethyl)indole-5-aceticacid;

2-(2-(3-Phenyl-7-propylbenz[4,5]isoxazol-6-yloxy)ethyl)indole-5-aceticacid;

2-(2-(3-Neopentyl-7-propylbenzofuran-6-yloxy)ethyl)-indole-5-(2,2-dimethyl)aceticacid;

2-(2-(3-Phenyl-7-propylbenz[4,5]isoxazol-6-yloxy)ethyl)-indole-5-propan-3-oicacid;

2-(2-(3-Neopentyl-7-propylbenz[4,5]isoxazol-6-yloxy)ethyl)-indole-5-propan-3-oicacid;

2-(2-(3-Phenyl-7-propylbenzofuran-6-yloxy)ethyl)-indole-5-oxyaceticacid;

2-(2-(3-Neopentyl-7-propylbenzofuran-6-yloxy)ethyl)-indole-5-oxyaceticacid;

N-[2-(2-(3-Phenyl-7-propylbenz[4,5]isoxazol-6-yloxy)ethyl)-indol-5-yl]glycine;

N-[2-(2-(3-Neopentyl-7-propylbenz[4,5]isoxazol-6-yloxy)ethyl)-indol-5-yl]glycine;

2-(2-(3-Phenyl-7-propylbenzofuran-6-yloxy)ethyl)-indole-6-acetic acid;

2-(2-(3-Neopentyl-7-propylbenzofuran-6-yloxy)ethyl)-indole-6-aceticacid;

2-(2-(3-Phenyl-7-propylbenz[4,5]isoxazol-6-yloxy)ethyl)-4-chloroindole-5-aceticacid;

2-(2-(3-Neopentyl-7-propylbenz[4,5]isoxazol-6-yloxy)ethyl)-4-chloroindole-5-aceticacid;

2-(2-(3-Phenyl-7-propylbenzofuran-6-yloxy)ethyl)-quinolin-6-acetic acid;

2-(2-(3-Neopentyl-7-propylbenzofuran-6-yloxy)ethyl)-quinolin-6-aceticacid;

2-(2-(3-Phenyl-7-propylbenz[4,5]isoxazol-6-yloxy)ethyl)-quinolin-7-aceticacid;

2-(2-(3-Neopentyl7-propylbenz[4,5]isoxazol-6-yloxy)ethyl)-quinolin-7-aceticacid;

2-(2-(3-Phenyl-7-propylbenzofuran-6-yloxy)ethyl)-quinazolin-6-aceticacid;

2-(2-(3-Neopentyl-7-propylbenzofuran-6-yloxy)ethyl)-quinazolin-6-aceticacid;

2-(2-(3-Phenyl-7-propylbenz[4,5]isoxazol-6-yloxy)ethyl)-quinazolin-7-aceticacid;

2-(2-(3-Neopentyl-7-propylbenz[4,5]isoxazol-6-yloxy)ethyl)-quinazolin-7-aceticacid;

2-(2-(3-Phenyl-7-propylbenzofuran-6-yloxy)ethyl)-3-methylindole-5-aceticacid;

2-(2-(3-Neopentyl-7-propylbenzofuran-6-yloxy)ethyl)-3-methylindole-5-aceticacid;

2-(2-(3-Phenyl-7-propylbenz[4,5]isoxazol-6-yloxy)ethyl)-3-butylindole-5-aceticacid;

2-(2-(3-Neopentyl-7-propylbenz[4,5]isoxazol-6-yloxy)ethyl)-3-butylindole-5-aceticacid;

2-(2-(3-Phenyl-7-propylbenzofuran-6-yloxy)ethyl)-7-propylindole-5-aceticacid;

2-(2-(3-Neopentyl-7-propylbenzofuran-6-yloxy)ethyl)-7-propylindole-5-aceticacid;

2-(2-(3-Phenyl-7-propylbenz[4,5]isoxazol-6-yloxy)ethyl)-N-methylindole-5-aceticacid;

2-(2-(3-Neopentyl-7-propylbenz[4,5]isoxazol-6-yloxy)ethyl)-N-methylindole-5-aceticacid;

2-(3-(3-Phenyl-7-propylbenzofuran-6-yloxy)propy)indole-5-acetic acid;

2-(3-(3-Neopentyl-7-propylbenzofuran-6-yloxy)propy)indole-5-acetic acid;

2-(2-(3-Phenyl-7-propylbenz[4,5]isoxazol-6-yloxy)propyl)indole-5-aceticacid;

2-(2-(3-Neopentyl-7-propylbenz[4,5]isoxazol-6-yloxy)propyl)indole-5-aceticacid;

2-(2-(3-Phenyl-7-(cyclopropylmethyl)benzofuran-6-yloxy)ethyl)indole-5-aceticacid;

2-(2-(3-Neopentyl-7-(cyclopropylmethyl)benzofuran-6-yloxy)ethyl)indole-5-aceticacid;

2-(2-(1-Phenyl-4-propylindol-5-yloxy)ethyl)indole-5-acetic acid;

2-(2-(1-Phenyl-4-propylindol-5-yloxy)ethyl)benzofuran-5-acetic acid;

2-(2-(1-Phenyl-4-propylindol-5-yloxy)ethyl)indole-5-oxyacetic acid;

2-(2-(1-Phenyl-4-propylindol-5-yloxy)ethyl)indole-5-propan-3-oic acid;

2-(2-(4-Phenoxy-3-propylphenoxy)ethyl)indole-5-acetic acid;

2-(2-(4-(4-Tolyloxy)-3-propylphenoxy)ethyl)indole-5-acetic acid;

2-(2-(4-Valeryl-3-propylphenoxy)ethyl)indole-5-acetic acid;

2-(2-(4-Benzoyl-3-propylphenoxy)ethyl)indole-5-acetic acid;

2-(2-(4-(N-Hydroxyimino)valeryl-3-propylphenoxy)ethyl)indole-5-aceticacid;

2-(2-(4-(N-Hydroxyimino)benzoyl-3-propylphenoxy)ethyl)indole-5-aceticacid;

2-(2-(3-(3-Fluorophenyl)-7-propylbenzofuran-6-yloxy)ethyl)indole-5-aceticacid;

2-(2-(3-(Phen-2-ethyl)-7-propylbenzofuran-6-yloxy)ethyl)indole-5-aceticacid;

2-(2-(3-(4-t-Butylphenyl)-7-propylbenz[4,5]isoxazol-6-yloxy)ethyl)indole-5-aceticacid;

2-(2-(3-(2,2-Dimethyl-2-phenylethyl)-7-propylbenz[4,5]isoxazol-6-yloxy)ethyl)indole-5-aceticacid;

2-(2-(4-Phenoxy-2-propylphenoxy)ethyl)indole-5-acetic acid sodium salt;

2-(2-(4-Phenoxy-2-propylphenoxy)ethyl)indole-5-acetic acid;

2-(2-(4-Phenoxy-2-propylphenoxy)ethyl)indole-5-acetic acid methyl ester;

2-(2-(3-(2-Phenyl)ethyl-7-(n-propyl)benz[4,5]isoxazol-6-yloxy)ethyl)indole-5-aceticacid;

2-(2-(4-Phenoxy-2-propylphenoxy)ethyl)benzofuran-5-acetic acid;

2-(2-(3-(2,2-Dimethylpropyl)-7-(n-propyl)benz[4,5]isoxazol-6-yloxy)ethyl)benzofuran-5-aceticacid;

2-(2-(3-Phenyl-7-(n-propyl)benz[4,5]isoxazol-6-yloxy)ethyl)benzofuran-5-aceticacid;

2-(2-(3-Phenyl-7-(n-propyl)benzofuran-6-yloxy)ethyl)-benzofuran-5-aceticacid;

2-(2-(4-Phenoxy-2-propylphenoxy)ethyl-6,7,8,9-tetrahydronaphtho[2,1-b]furan-7-carboxylicacid sodium salt;

2-(2-(3-Phenyl-7-(n-propyl)benz[4,5]isoxazol-6-yloxy)ethyl)-6,7,8,9-tetrahydronaphtho[2,1-b]furan-7-carboxylicacid; and

2-(2-(3-(2,2-Dimethylpropyl)-7-(n-propyl)benz[4,5]isoxazol-6-yloxy)ethyl)-6,7,8,9-tetrahydronaphtho[2,1-b]furan-7-carboxylicacid.

Preferred examples of the compounds of the invention are as follows:

2-(2-(3-Phenyl-7-propylbenzofuran-6-yloxy)ethyl)indole-5-acetic acid;

2-(2-(3-Neopentyl-7-propylbenzofuran-6-yloxy)ethyl)indole-5-acetic acid;

2-(2-(3-Phenyl-7-propylbenzisoxazol-6-yloxy)ethyl)indole-5-acetic acid;

2-(2-(3-Neopentyl-7-propylbenzisoxazol-6-yloxy)ethyl)indole-5-aceticacid;

2-(2-(3-Phenyl-7-propylbenzofuran-6-yloxy)ethyl)benzothiophen-5-aceticacid;

2-(2-(3-Neopentyl-7-propylbenzofuran-6-yloxy)ethyl)benzofuran-5-aceticacid;

2-(2-(3-Phenyl-7-propylbenzisoxazol-6-yloxy)ethyl)benzofuran-5-aceticacid;

2-(2-(3-Neopentyl-7-propylbenzisoxazol-6-yloxy)ethyl)benzothiophen-5-aceticacid;

2-(2-(4-Phenoxy-2-propylphenoxy)ethyl)indole-5-acetic acid;

2-(2-(4-Phenoxy-2-propylphenoxy)ethyl)indole-5-acetic acid methyl ester;

2-(2-(3-(2-Phenyl)ethyl-7-(n-propyl)benz[4,5]isoxazol-6-yloxy)ethyl)indole-5-aceticacid;

2-(2-(4-Phenoxy-2-propylphenoxy)ethyl)benzofuran-5-acetic acid;

2-(2-(3-(2,2-Dimethylpropyl)-7-(n-propyl)benz[4,5]isoxazol-6-yloxy)ethyl)benzofuran-5-aceticacid;

2-(2-(3-Phenyl-7-(n-propyl)benz[4,5]isoxazol-6-yloxy)ethyl)benzofuran-5-aceticacid;

2-(2-(3-Phenyl-7-(n-propyl)benzofuran-6-yloxy)ethyl)-benzofuran-5-aceticacid;

2-(2-(4-Phenoxy-2-propylphenoxy)ethyl-6,7,8,9-tetrahydronaphtho[2,1-b]furan-7-carboxylicacid sodium salt;

2-(2-(3-Phenyl-7-(n-propyl)benz[4,5]isoxazol-6-yloxy)ethyl)-6,7,8,9-tetrahydronaphtho[2,1-b]furan-7-carboxylicacid; and

2-(2-(3-(2,2-Dimethylpropyl)-7-(n-propyl)benz[4,5]isoxazol-6-yloxy)ethyl)-6,7,8,9-tetrahydronaphtho[2,1-b]furan-7-carboxylicacid.

More preferred compounds are as follows:

2-(2-(4-Phenoxy-2-propylphenoxy)ethyl)indole-5-acetic acid;

2-(2-(4-Phenoxy-2-propylphenoxy)ethyl)indole-5-acetic acid methyl ester;

2-(2-(3-(2-Phenyl)ethyl-7-(n-propyl)benz[4,5]isoxazol-6-yloxy)ethyl)indole-5-aceticacid and

2-(2-(4-Phenoxy-2-propylphenoxy)ethyl-6,7,8,9-tetrahydronaphtho[2,1-b]furan-7-carboxylicacid sodium salt.

The compounds of the present invention may have asymmetric centers andoccur as racemates, racemic mixtures, and as individual diastereomers,with all possible isomers, including optical isomers, being included inthe present invention.

Compounds of the general Formula I or Ia may be separated intodiastereoisomeric pairs of enantiomers by, for example, fractionalcrystallization from a suitable solvent, for example methanol or ethylacetate or a mixture thereof. The pair of enantiomers thus obtained maybe separated into individual stereoisomers by conventional means, forexample by the use of an optically active acid as a resolving agent.

Alternatively, any enantiomer of a compound of the general Formula I orIa may be obtained by stereospecific synthesis using optically purestarting materials of known configuration.

The instant compounds can be isolated in the form of theirpharmaceutically acceptable acid addition salts, such as the saltsderived from using inorganic and organic acids. Examples of such acidsare hydrochloric, nitric, sulfuric, phosphoric, formic, acetic,trifluoroacetic, propionic, maleic, succinic, malonic and the like. Inaddition, certain compounds containing an acidic function such as acarboxy or tetrazole, can be isolated in the form of their inorganicsalt in which the counterion can be selected from sodium, potassium,lithium, calcium, magnesium and the like, as well as from organic bases.

As previously indicated, the compounds of the present invention havevaluable pharmacological properties. They are useful in treating orpreventing diabetes and related diseases such as diabetic retinopathy,diabetic nephropathy and the like, treating obesity, loweringtriglyceride levels and preventing vascular restenosis, and treatingpancreatitis. They are useful in treating other disorders where insulinresistance is a component including ovarian hyperandrogenism (polycycticovarian syndrome). They are also useful in raising high densitylipoprotein levels, preventing, halting or slowing the progression ofatherosclerotic cardiovascular diseases and related conditions anddisease events.

The present invention further provides a compound of the general FormulaI or Ia, or a pharmaceutically acceptable salt or ester thereof, for usein the treatment of hyperglycemia (diabetes) in human or non-humananimals.

The present invention further provides a compound of the general FormulaI or Ia, or a pharmaceutically acceptable salt or ester thereof, incombination with sulfonylureas, biguanides, α glucosidase inhibitors,other insulin secretogogue or insulin for use in the treatment ofdiabetes and related diseases such as diabetic retinopathy; diabeticnephropathy and the like; pancreatitis; obesity, lowering triglyceridelevels, vascular restenosis, other disorders where insulin resistance isa component, such as ovarian hyperandrogenism (polycyctic ovariansyndrome), raising high density lipoprotein levels, and preventing,halting or slowing the progression of atherosclerotic cardiovasculardiseases and related conditions and disease events and hypertension inhuman or non-human animals.

In one aspect, the present invention provides a compound of Formula I orIa for use in the treatment of obesity in human or non-human animals.Said compound can be effectively used in combination with other known orproposed strategies for the treatment of obesity or obesity-relateddisorders; for example, fenfluramine, dexfenfluramine, phentermine andβ₃ adrenergic receptor agonist agents.

Diabetes mellitus is characterized by metabolic defects in productionand utilization of glucose which result in the failure to maintainappropriate blood sugar levels. The result of these defects is elevatedblood glucose or hyperglycemia. Research on the treatment of diabeteshas centered on attempts to normalize fasting and postprandial bloodglucose levels. Treatments have included parenteral administration ofexogenous insulin, oral administration of drugs and dietary therapies.The instant compounds can be effectively used alone as well as incombination with known therapies for diabetes including insulin,sulfonylureas, biguanides (such as metformin), α-glucosidase inhibitors(such as acarbose) and others.

Two major forms of diabetes mellitus are now recognized. Type Idiabetes, or insulin-dependent diabetes, is the result of a deficiencyof insulin, the hormone which regulates glucose utilization. Type IIdiabetes, or non-insulin dependent diabetes, often occurs in the face ofnormal, or even elevated levels of insulin and appears to be the resultof the inability of tissue to respond appropriately to insulin. MostType II diabetics are also obese. Accordingly, an aspect the presentinvention provides a method of lowering triglyceride levels whichcomprises administering, to a mammal in need thereof, a therapeuticallyeffective amount of a compound of the formula I or Ia orpharmaceutically acceptable salt or ester thereof.

In addition the compounds of the present invention lower or modulatetriglyceride levels and/or cholesterol levels and raise HDL plasmalevels and are therefore of use in treating medical conditions whereinsuch lowering (and raising) is thought to be beneficial. Thus they maybe used in the treatment of hypertension, obesity, atheroscleroticdisease events, diabetes and related conditions by administering to amammal in need of such treatment, a therapeutically effective amount ofa compound of formula I or Ia or a pharmaceutically acceptable saltthereof.

The compositions are comprised of a compound of formula I or Ia incombination with a carrier. They may also contain other activeingredients known for use in the treatment of atherosclerotic diseaseevents, diabetes, hypertension, obesity and related conditions, forexample, fibrates such as clofibrate, bezafibrate and gemfibrozil;inhibitors of cholesterol biosynthesis, such as HMG-CoA reductaseinhibitors, for example, lovastatin, simvastatin and pravastatin;inhibitors of cholesterol absorption, for example, beta-sitosterol, and(acyl CoA:cholesterol acyltransferase) inhibitors, for example,melinamide; anion exchange resins, for example, cholestyramine,colestipol or a dialkylaminoalkyl derivatives of a cross-linked dextran;nicotinyl alcohol, nicotinic acid or a salt thereof; vitamin E; andthyromimetics.

In particular the invention provides methods for preventing or reducingthe risk of developing atherosclerosis, comprising the administration ofa prophylactically effective amount of a compound of formula I or Iaalone or in combination with one or more additional pharmaceuticallyactive agents, to a mammal, particularly human, who is at risk ofdeveloping atherosclerosis.

Atherosclerosis as used herein encompasses vascular diseases andconditions that are recognized and understood by practicing physicians.Atherosclerotic cardiovascular disease, coronary heart disease (alsoknown as coronary artery disease or ischemic heart disease),cerebrovascular disease and peripheral vessel disease are all clinicalmanifestations of atherosclerosis and are therefore encompassed by theterms “atherosclerosis” and “atherosclerotic disease.”

The instant invention further provides methods for preventing orreducing the risk of a first or subsequent (where the potential existsfor recurrence) atherosclerotic disease event, comprising theadministration of a prophylactically effective amount, or moreparticularly, an anti-atherosclerotic effective amount of cholesterolbiosynthesis inhibitor, of a compound of formula I or Ia alone or incombination with one or more additional pharmaceutically active agents,to a mammal, particularly human, who is at risk for having anatherosclerotic disease event. The term “atherosclerotic disease event”as used herein is intended to encompass coronary heart disease events,cerebrovascular events, and intermittent claudication. Coronary heartdisease events are intended to include CHD death, myocardial infarction(i.e., a heart attack), and coronary revascularization procedures.Cerebrovascular events are intended to include ischemic or hemorrhagicstroke (also known as cerebrovascular accidents) and transient ischemicattacks. Intermittent claudication is a clinical manifestation ofperipheral vessel disease. It is intended that persons who havepreviously experienced one or more non-fatal atherosclerotic diseaseevent are those for whom the potential for recurrence of such an eventexists.

Persons to be treated with the instant therapy include those at risk ofdeveloping atherosclerotic disease and of having an atheroscleroticdisease event. Standard atherosclerotic disease risk factors are knownto the average physician practicing in the relevant fields of medicine.Such known risk factors include but are not limited to hypertension,smoking, diabetes, low levels of high density lipoprotein cholesterol,high levels of low density lipoprotein cholesterol, and a family historyof atherosclerotic cardiovascular disease. Published guidelines fordetermining those who are at risk of developing atherosclerotic diseasecan be found in: National Cholesterol Education Program, Second reportof the Expert Panel on Detection, Evaluation, and Treatment of HighBlood Cholesterol in Adults (Adult Treatment Panel II), NationalInstitute of Health, National Heart Lung and Blood Institute, NIHPublication No. 93-3095, September 1993; abbreviated version: ExpertPanel on Detection, Evaluation, and Treatment of High Blood Cholesterolin Adults, Summary of the second report of the national cholesteroleducation program (NCEP) Expert Panel on Detection, Evaluation, andTreatment of High Blood Cholesterol in Adults (Adult Treatment PanelII), JAMA, 1993, 269, pp. 3015-23. People identified as having one ormore of the above-noted risk factors, as well as people who already haveatherosclerosis, are intended to be included within the group of peopleconsidered to be at risk for having an atherosclerotic disease event.

The compounds of the present invention may be orally administered as apharmaceutical composition, for example, with an inert diluent, or withan edible carrier, or they may be enclosed in hard or soft shellcapsules, or they may be compressed into tablets, or incorporateddirectly into food. For oral therapeutic administration, which includessublingual administration, these active compounds may be incorporatedwith excipients and used in the form of tablets, capsules, ampules,sachets, elixirs, suspensions, syrups and the like. Such compositionsand preparations may contain, e.g., at least about 0.1 percent of activecompound. The percentage of active compound in these compositions may,of course, be varied and may conveniently be between about 2 percent toabout 90 percent of the weight of the unit. The active compounds canalso be administered intranasally as, for example, liquid drops orspray.

The effective dosage of active ingredient employed may vary depending onthe particular compound employed, the mode of administration, thecondition being treated and the severity of the condition.

When treating or preventing diabetes mellitus and/or hyperglycemia orhypertriglyceridemia, or obesity, or when treating, preventing orslowing the progression of atherosclerosis, generally satisfactoryresults are obtained when the compounds are administered at a dailydosage of from about 0.1 milligram to about 100 milligrams per kilogramof animal body weight, preferably given as a single daily dose or individed doses two to six times a day, or in sustained release form. Formost large mammals, the total daily dosage is from about 1.0 milligramsto about 1000 milligrams, preferably from about 1 milligrams to about 50milligrams. In the case of a 70 kg adult human, the total daily dosewill generally be from about 7 milligrams to about 350 milligrams. Thisdosage regimen may be adjusted to provide the optimal therapeuticresponse.

The compounds of the instant invention may be used effectively alone orin combination with one or more additional active agents depending onthe desired target therapy. Combination therapy includes administrationof a single pharmaceutical dosage formulation which contains a compoundof formula I or Ia and one or more additional active agents, as well asadministration of a compound of formula I or Ia and each active agent inits own separate pharmaceutical dosage formulation. For example, acompound of formula I or Ia and an HMG-CoA reductase inhibitor can beadministered to the patient together in a single oral dosage compositionsuch as a tablet or capsule, or each agent administered in separate oraldosage formulations. Where separate dosage formulations are used, acompound of formual I or Ia and one or more additional active agents canbe administered at essentially the same time, i.e., concurrently, or atstaggered times, i.e, sequentially. Combination therapy is understood toinclude all these regimens.

An example of combination treatment or prevention of atherosclerosis maybe wherein a compound of formula I or Ia is administered in combinationwith one or more of the following active agents: an antihyperlipidemicagent; a plasma HDL-raising agent; an antihypercholesterolemic agentsuch as a cholesterol biosynthesis inhibitor, for example an HMG-CoAreductase inhibitor, an HMG-CoA synthase inhibitor, a squalene epoxidaseinhibitor, or a squalene synthetase inhibitor (also known as squalenesynthase inhibitor); an acyl-coenzyme A: cholesterol acyltransferase(ACAT) inhibitor such as melinamide; probucol; nicotinic acid and thesalts thereof and niacinamide; a cholesterol absorption inhibitor suchas beta-sitosterol; a bile acid sequestrant anion exchange resin such ascholestyramine, colestipol or dialkylaminoalkyl derivatives of across-linked dextran; an LDL (low density lipoprotein) receptor inducer;fibrates such as clofibrate, bezafibrate, fenofibrate, and gemfibrizol;vitamin B₆ (also known as pyridoxine) and the pharmaceuticallyacceptable salts thereof such as the HCl salt; vitamin B₁₂ (also knownas cyanocobalamin); anti-oxidant vitamins such as vitamin C and E andbeta carotene; a beta-blocker; an angiotensin II antagonist; anangiotensin converting enzyme inhibitor; and a platelet aggregationinhibitor such as fibrinogen receptor antagonists (i.e., glycoproteinIIb/IIIa fibrinogen receptor antagonists) and aspirin. As noted above,the compounds of formula I or Ia can be administered in combination withmore than one additional active agent, for example, a combination of acompound of formula I or Ia with an HMG-CoA reductase inhibitor (e.g.lovastatin, simvastatin and pravastatin) and aspirin, or a compound offormula I or Ia with an HMG-CoA reductase inhibitor and a betaadrenergic blocking drug.

Another example of combination therapy can be seen in treating obesityor obesity-related disorders, wherein the compounds of formula I or Iamay be effectively used in combination with for example, fenfluramine,dexfenfluramine, phentermine and β₃ adrenergic receptor agonist agents.

Still another example of combination therapy can be seen in treatingdiabetes and related disorders wherein the compounds of formula I or Iacan be effectively used in combination with for example sulfonylureas,biguanides, α-glucosidase inhibitors, other insulin secretogogues,insulin as well as the active agents discussed above for treatingatherosclerosis.

In accordance with this invention, a pharmaceutically effective amountof a compound of formula I or Ia can be used for the preparation of amedicament useful for treating diabetes, treating obesity, loweringtryglyeride levels, raising the plasma level of high densitylipoprotein, and for treating, preventing or reducing the risk ofdeveloping atherosclerosis, and for preventing or reducing the risk ofhaving a first or subsequent atherosclerotic disease event in mammals,particularly in humans.

Additionally, an effective amount of a compound of formula I or Ia and atherapeutically effective amount of one or more active agents selectedfrom the group consisting of: an antihyperlipidemic agent; a plasmaHDL-raising agent; an antihypercholesterolemic agent such as acholesterol biosynthesis inhibitor, for example an HMG-CoA reductaseinhibitor, an HMG-CoA synthase inhibitor, a squalene epoxidaseinhibitor, or a squalene synthetase inhibitor (also known as squalenesynthase inhibitor); an acyl-coenzyme A: cholesterol acyltransferaseinhibitor; probucol; nicotinic acid and the salts thereof; niacinamide;a cholesterol absorption inhibitor; a bile acid sequestrant anionexchange resin; a low density lipoprotein receptor inducer; clofibrate,fenofibrate, and gemfibrozol; vitamin B₆ and the pharmaceuticallyacceptable salts thereof; vitamin B₁₂; an anti-oxidant vitamin; abeta-blocker; an angiotensin II antagonist; an angiotensin convertingenzyme inhibitor; a platelet aggregation inhibitor; a fibrinogenreceptor antagonist; aspirin; fenfluramine, dexfenfluramine,phentermine, β₃ adrenergic receptor agonists; sulfonylureas, biguanides,α-glucosidase inhibitors, other insulin secretogogues and insulin can beused together for the preparation of a medicament useful for theabove-described treatments.

The tablets, capsules and the like may also contain a binder such astragacanth, acacia, corn starch or gelatin; excipients such as dicalciumphosphate; a disintegrating agent such as corn starch, potato starch oralginic acid; a lubricant such as magnesium stearate; and a sweeteningagent such as sucrose, lactose or saccharin. When a dosage unit is inthe form of a capsule, it may also contain a liquid carrier, such as afatty oil.

Various other materials may be present as coatings or to modify thephysical form of the dosage unit. For instance, tablets may be coatedwith shellac, sugar or both. A syrup or elixir may contain, in additionto the active ingredient, sucrose as a sweetening agent, methyl andpropylparabens as preservatives, a dye and a flavoring such as cherry ororange flavor.

The compounds of the present invention may also be administeredparenterally, i.e, intramuscularly, intravenously, transdermally orsubcutaneously. Solutions or suspensions of these active compounds canbe prepared in water suitably mixed with a surfactant such ashydroxy-propylcellulose. Dispersions can also be prepared in glycerol,liquid polyethylene glycols and mixtures thereof in oils. Under ordinaryconditions of storage and use, these preparations may contain apreservative to prevent the growth of microorganisms.

The pharmaceutical forms suitable for injectable use include sterileaqueous solutions or dispersions and sterile powders for theextemporaneous preparation of sterile injectable solutions ordispersions. In all cases, the form must be sterile and must be fluid tothe extent that easy syringability exists. It must be stable under theconditions of manufacture and storage and must be preserved against thecontaminating action of microorganisms such as bacteria and fungi. Thecarrier can be a solvent or dispersion medium containing, for example,water, ethanol, polyol (e.g. glycerol, propylene glycol and liquidpolyethylene glycol), suitable mixtures thereof, and vegetable oils.

Specific examples of formula I or Ia may require the use of protectinggroups to enable their successful elaboration into the desiredstructure. Protecting groups may be chosen with reference to Greene, T.W., et al., Protective Groups in Organic Synthesis, John Wiley & Sons,Inc., 1991. The blocking groups are readily removable, i.e., they can beremoved, if desired, by procedures which will not cause cleavage orother disruption of the remaining portions of the molecule. Suchprocedures include chemical and enzymatic hydrolysis, treatment withchemical reducing or oxidizing agents under mild conditions, treatmentwith fluoride ion, treatment with a transition metal catalyst and anucleophile, and catalytic hydrogenation.

Non-limiting examples of suitable hydroxyl protecting groups are:trimethylsilyl, triethylsilyl, o-nitrobenzyloxycarbonyl,p-nitrobenzyloxycarbonyl, t-butyldiphenylsilyl, t-butyldimethylsilyl,benzyloxycarbonyl, t-butyloxycarbonyl, 2,2,2-trichloroethyloxycarbonyl,and allyloxycarbonyl. Non-limiting examples of suitable carboxylprotecting groups are benzhydryl, o-nitrobenzyl, p-nitrobenzyl,2-naphthylmethyl, allyl, 2-chloroallyl, benzyl, 2,2,2-trichloroethyl,trimethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl,2-(trimethylsilyl)ethyl, phenacyl, p-methoxybenzyl, acetonyl,p-methoxyphenyl, 4-pyridylmethyl and t-butyl.

The process for making the compounds of the instant invention isgenerally depicted in Scheme 1 and 2 below:

The invention is further illustrated in connection with the followingnon-limiting examples.

EXAMPLE 1

2-(2-(3-Phenyl-7-propylbenzofuran-6-yloxy)ethyl)indole-5-acetic Acid

Step A: Preparation of Methyl 4-amino-3-bromophenylacetate

To a suspension of 4-aminophenylacetic acid (7.4 g; 59.0 mmol) in ca. 90ml of methanol, was added ca. 6.0 ml of concentrated sulfuric acid.After refluxing the brown solution for 2.5 hrs, it was concentrated to adark oil. The oil was diluted with water and basified with 10 wt %NaHCO₃ to pH 9 and extracted with ethyl acetate. The organic layer waswashed with water, brine and dried with Na₂SO₄. Evaporation in vacuoafforded 5.0 g of methyl 4-aminophenylacetate as a dark oil.

Without further purification the oil (5.0 g; 30.3 mmol) was diluted with300 ml of THF. To this solution was added dropwise over 1 hour, asolution of pyridinium bromide perbromide (9.69 g; 30.3 mmol) in 300 mlof THF at room temperature. The light tan suspension was filtered andthe filter cake was washed with ethyl acetate (2 times). The filtratewas treated with solid sodium bisulfite until the color faded,concentrated to an oil and diluted with ethyl acetate (ca. 200 ml). Theorganic layer was washed, dried (Na₂SO₄) and concentrated to a dark oil.The filter cake was dissolved in water, neutralized with 1 M sodiumbicarbonate and extracted with ethyl acetate. The extracts were washedwith water, dried (Na₂SO₄) and evaporated in vacuo to an oily residue,which was combined with the filtrate residue. Chromatography (silicagel, hexane:ethyl acetate::4:1) afforded 5.93 g of the title compound.

NMR (CDCl₃): δ7.34 (s,1H); 7.03 (d,1H); 6.72 (d,1H); 3.69 (s,3H); 3.50(s, 2H)

Step B: Preparation of 1-(t-Butyldimethylsilyloxy)-3-butyne

To a solution of 3-butyne-1-ol (5.0 g; 71.3 mmol) in ca. 75 ml ofmethylene chloride was added tert-butydimethylsilyl chloride (10.8 g;71.6 mmol) and 7 ml of pyridine. The mixture was allowed to stirovernight at room temperature, diluted with methylene chloride, washedwith water, 1M HCl, brine and dried (Na₂SO₄). Concentration in vacuoafforded the title compound as a colorless liquid.

NMR (CDCl₃): δ3.75 (t,2H); 2.41 (m,2H); 1.97 (s,1H); 0.91 (s,9H); 0.10(s,6H)

Step C: Preparation of the Methyl4-amino-3-(3-t-butyldimethylsilyloxy)-1-butynyl)phenylacetate

Methyl 4-amino-3-(3-t-butyldimethylsilyloxy)-1-butynyl)phenylacetate(1.0 g, 4.1 mmol), 1-(t-butyldimethylsilyloxy)-3-butyne (840 mg, 4.55mmol), dichlorobis(triphenylphosphine)-palladium(II) catalyst (57 mg, 2mol %), copper(I) iodide (31 mg, 4 mol %) and ca. 10 ml of diethylaminewere combined and heated at reflux overnight. The mixture wasconcentrated and purified by chromatography (silica gel, hexane:ethylacetate 9:1 to 4:1) to afford 560 mg of the title compound as a darkliquid.

NMR (CDCl₃): δ7.17 (s,1H); 7.01 (d,1H); 6.66 (d, 1H); 3.85 (t,2H); 3.69(s,3H); 3.48 (s,2H); 2.49 (t,2H); 0.91 (s,9H); 0.10 (s,6H)

Step D: Preparation of the Methyl2-(2-(t-butyldimethylsilyloxyethyl)indole-5-acetate

A mixture of methyl4-amino-3-(3-t-butyldimethyl-silyloxy)-1-butynyl)phenylacetate (560 mg;1.67 mmol), in acetonitrile (5 mL), and bis(acetonitrile)palladium(II)chloride (20 mg, ca. 5 mol %) were combined and heatedunder reflux for 30 minutes, concentrated and flash chromatographed(silica gel, hexane:ethyl acetate 9:1 to 4:1) to yield 417 mg of thetitle compound.

NMR (CDCl₃): δ7.45 (s,1H); 7.25 (d,1H); 7.19 (d,1H); 6.20 (s,1H); 3.94(t,2H); 3.69 (s, 5H); 2.98 (t, 2H); 0.91 (s, 9H); 0.10 (s, 6H)

Step E: Preparation of the Methyl 2-(2-hydroxyethyl)indole-5-acetate

To a solution of methyl2-(2-(t-butyldimethylsilyl-oxyethyl)-indole-5-acetate (400 mg; 1.15mmol) in ca. 4 ml of THF was added a 1 M tetrabutylammonium fluoride inTHF (1.2 mL; 1.05 eq) at 0° C. After 15 minutes, the reaction wasallowed to warm to room temperature and stirred for an additional 3hours. It was concentrated, diluted with water and extracted with ethylacetate. The organic layer was washed with water, dried (Na₂SO₄),concentrated and chromatographed (silica gel, hexane:ethyl acetate 4:1)to yield 241 mg of the title compound as a colorless oil.

NMR (CDCl₃): δ7.45 (s,1H); 7.25 (d,1H); 7.19 (d,1H); 6.25 (s,1H); 3.80(t,2H); 3.70 (s, 5H); 2.95 (t, 2H)

Step F: Preparation of Methyl2-(2-(3-phenyl-7-propylbenzofuran-6-yloxy)-ethyl)-indole-5-acetate

To a solution of the methyl 2-(2-hydroxyethyl)indole-5-acetate (37.6 mg;0.16 mmol), Ph₃P (47 mg; 1.1 eq), 3-phenyl-6-hydroxy-7-propylbenzofuran(45 mg; 1.1 eq) and THF (5 mL) was added diisopropyl azodicarboxylate(35 μL; 1.1 eq), and the mixture was stirred at room temperatureovernight. The mixture was concentrated and chromatographed (silica gel,hexane:ethyl acetate::9:1 to 4:1) affording 18.6 mg of the titlecompound.

NMR (CDCl₃): δ7.77 (s,1H); 7.65 (d,1H); 7.40 (d,1H); 7.45 (d,1H); 6.93(d,1H); 6.33 (s,1H); 4.37 (t,2H); 3.74 (s,2H); 3.70 (s, 3H); 3.32(t,2H); 2.97 (t, 2H)

Step G: Preparation of2-(2-(3-Phenyl-7-propylbenzofuran-6-yloxy)ethyl)indole-5-acetic Acid

A solution of 18.6 mg (39.8 mmol) of methyl2-(2-(3-phenyl-7-propylbenzofuran-6-yloxy)-ethyl)-indole-5-acetate inca. 2.0 ml of methanol and 1 M aqueous LiOH (79.6 uL) was heated at 60°C. for 16 hours. The mixture was diluted with ethyl acetate andacidified to pH 5-6 with 1 M HCl, washed with water (2 times), brine (1time) and dried over sodium sulfate and concentrated to afford 11.6 mgof the title compound. (mp=129-130° C.).

Mass Spec=471.3, calc=453.54+NH₄).

NMR (CDCl₃): δ7.77 (s,1H); 7.65 (d,1H); 7.40 (d,1H); 7.45 (d,1H); 6.93(d,1H); 6.33 (s,1H); 4.37 (t,2H); 3.73 (s,2H); 3.30 (t,2H); 2.98 (t, 2H)

EXAMPLE 2

2-(2-(3-(2,2-Dimethylpropyl)-7-propylbenz[4,5]isoxazol-6-yloxy)ethyl)indole-5-aceticAcid

Using the procedures in Example 1, steps F and G, the title compound wasprepared from methyl 2-(2-hydroxyethyl)indole-5-acetate and3-(2,2-dimethylpropyl)-7-propyl-6-hydroxybenz[4,5]isoxazole.

(dcp=110° C.; Mass Spec=449.4 (m+1), calc=448.6);

NMR (CDCl₃): δ8.35 (bs,1H); 7.40 (d,1H); 7.29 (m,1H); 7.07 (d,1H); 6.95(d,1H); 6.33 (s,1H); 4.36 (t,2H); 3.73 (s,2H); 2.93 (t, 2H)

EXAMPLE 3

2-(2-(3-Phenyl-7-propylbenz[4,5]isoxazol-6-yloxy)ethyl)indole-5-aceticAcid

Using the procedures in Example 1, steps F and G, the title compound wasprepared from methyl 2-(2-hydroxyethyl)indole-5-acetate and3-phenyl-7-propyl-6-hydroxybenz[4,5]isoxazole as a colorless gum.

(Mass Spec=455 456(m+1), calc=453.5).

NMR (CDCl₃): δ7.95 (d,1H); 7.70 (d,1H); 7.55 (m,3H); 7.29 (d,2H); 7.10(d,1H); 6.90 (d,1H); 6.33 (s,1H); 4.39 (t,2H); 3.70 (t,2H); 2.98 (t, 2H)

EXAMPLE 4

Step A: 4-Phenoxyphenyl Allyl Ether

To a solution of the 4-phenoxyphenol (100 g, 0.54 mole) in acetone (500mL) was added potassium carbonate (148 g, 1.07 mol) and allyl bromide(55.8 mL, 0.64 mole) and the resulting suspension heated to reflux.After 24 hours, the reaction was cooled to 0° C. and filtered. Thefilter cake was washed with ethyl acetate and the filtrate wasconcentrated to give a yellow oil which was partitioned between ethylacetate (500 mL) and water (500 mL). The phases were separated and theorganic washed with brine, dried and concentrated to give the allylether as a yellow oil (131 g).

Step B: 2-Allyl-4-phenoxyphenol

Claisen rearrangement: The allyl ether (131.6 g, 0.52 mole) was takeninto 1,2-dichlorobenzene (600 mL) and the solution was heated to reflux.Approximatly 100 mL of distillate was removed to insure the completeremoval of any residual ethyl acetate and the remaining solution left atreflux overnight. The reaction was then cooled and diluted with 3.5liters of hexanes and 2N NaOH (1.8 liter) was added. The aqueous phasewas removed and the organic extracted twice more with 900 mL portions of2N NaOH. The combined aqueous solutions were then adjusted to pH˜1 with2N HCl and extracted with ether (1×2 liter). The ether extract wasdried, filtered and concentrated to give an orange oil. (141.4 g).

Step C: 4-Phenoxy-2-propylphenol

The phenol of Step B (141.4 g, 0.62 mole) was taken into 2 liters ofethyl acetate and the reaction vessel charged with 10% Pd/C catalyst (12g). The reaction was stirred under H₂ until the starting material wasconsumed. The reaction mixture was filtered through Celite and the cakewashed with ethyl acetate (total volume ˜6 liters). The filtrate wasconcentrated to a dark oil which was taken into ether (1500 mL) andwashed with 2N HCl (200 mL) sat'd. sodium bicarbonate and brine. Theorganic solution was dried over magnesium sulfate, filtered andconcentrated to give a light brown oil. (125 g).

Step D: 2-(2-(4-Phenoxy-2-propylphenoxy)ethyl)indole-5-acetic Acidmethyl Ester

A solution of methyl 2-(2-hydroxyethyl)indole-5-acetate from Example 1,Step E (7.6 g), 4-phenoxy-2-propylphenol (8.28 g), triphenylphosphine(11.2 g), DIAD (8.5 mL) and THF (125 mL) was stirred under nitrogen atroom temperature. After stirring overnight none of the starting indoleremained as determined by TLC and the reaction was concentrated to ayellow oil. The oil was purified by silca gel chromatography (10%-20%ethyl acetate in hexanes) to give the desired product (9.0 g).

Step E: 2-(2-(4-Phenoxy-2-propylphenoxy)ethyl)indole-5-acetic AcidSodium Salt

The ester (9.0 g) was taken into methanol (390 mL) and treated with 1MLiOH (51 mL) and the resulting solution was warmed to 60° C. Afterheating overnight there was no starting material remaining by TLC. Thereaction was concentrated and the residue treated with 2N NaOH (26 mL)and then extracted with ethyl acetate (×2). The organic extracts werecombined washed with water, brine dried and concentrated to give anoff-white foam (8.9 g). This material was then taken into anhydrousmethanol (170 mL) and treated with 0.5M NaOMe (41.4 mL). After stirringat room temperature for 20 min the reaction was concentrated to give aslightly yellow foam. (7.2 g).

Step F: Formation of the Crystalline Salt

The salt form of the compound can be protonated as shown in thefollowing:

wherein X represents a positively charged counterion such as Na⁺, K⁺ andothers known in the art. The salt forms can also be present in the formof a solvate.

In the case of Na⁺, the sodium salt (5.23 g) was taken into 52.3 mL HPLCgrade water and the solids dissolved upon heating to reflux. The darkbrown solution was allowed to cool to 20° C. and then seeded. After 30min visible solids are floating in the solution, after 1.25 there is aconsiderable amount of colorless solids present. After standing 18 hrs,the colorless solid is filtered from solution to give a crystallinecompound pentahydrate.

(mp=86-87° C. Mass Spec=428.51.

NMR (CDCl₃):8.28 (s,1H); 7.41 (s,1H); 7.32-7.27 (m,3H); 7.18 (d,1H);7.04 (t,1H); 6.99 (d,1H); 6.95 (d,1H); 6.89 (s,1H); 6.81 (dd, 1H); 6.77(d, 1H); 6.27 (s, 1H); 4.19 (t, 2H); 3.61 (s, 1H); 3.21 (t, 2H); 2.63(t,2H); 1.67-1.60 (m, 2H), 0.97 (t, 3H).

The pentahydrate above is but one crystal form. The compounds of theinstant invention are intended to include all crystalline forms and areuseful in various pharmaceutically acceptable salt forms, for thesynthesis of antidiabetic compounds that are in turn useful for thetreatment of the diseases disclosed herein in animal and human subjects.The term “pharmaceutically acceptable salt” refers to those salt formswhich would be apparent to the pharmaceutical chemist. i.e., those whichare substantially non-toxic and which provide the desiredpharmacokinetic properties, palatability, absorption, distribution,metabolism or excretion. Other factors, more practical in nature, whichare also important in the selection, are cost of the raw materials, easeof crystallization, yield, stability, hygroscopicity and flowability ofthe resulting bulk drug.

The crystalline forms of the compound are characterized below by virtueof their X-Ray Powder Diffraction (XRPD) patterns. The XRPD patterns arecollected on a Philips APD 3720 automated powder diffractometer. Thex-ray generator employs a copper target, an accelerating potential of 45kV and a filament emission of 40 mA. Diffraction patterns are collectedfrom 2° C. to 40° C.

The sodium salt of the compound (unsolvated material) was characterizedas having an XRPD pattern at 5.5, 5.3, 4.9, 4.3, 4.1, 3.9, 3.8, 3.7,3.6, 3.3, 3.2, 2.9, 2.6 and 2.3 angstroms. More complete XRPD datapertaining to the compound is shown below in Table 1.

TABLE 1 Tip Peak Angle Width Peak Backg D Spac I/I max Type No. (deg)(deg) (cts) (cts) (Ang) (%) A1 A2 Ot Sign 1 8.3325 0.48 10. 6. 10.60282.34 x x 0.83 2 9.7600 0.12 19. 7. 9.0550 4.43 x x 0.89 3 12.1375 0.3610. 8. 7.2861 2.34 x x 1.05 4 14.1525 0.15 17. 9. 6.2529 3.85 x x 0.91 516.1575 0.15 46. 12. 5.4812 10.59 x x 2.09 6 16.6450 0.15 53. 12. 5.321812.20 x x 1.02 7 16.8200 0.15 41. 12. 5.2668 9.38 x x 0.91 8 17.62500.24 30. 13. 5.0280 6.93 x x 1.26 9 18.2600 0.07 154. 13. 4.8546 35.20 xx 1.38 10 18.9025 0.18 17. 14. 4.6910 3.85 x x 1.26 11 19.5625 0.12 34.14. 4.5342 7.70 x x 0.76 12 20.5175 0.09 117. 15 4.3252 26.70 x x 1.0713 21.6225 0.21 48. 16 4.1066 10.90 x x 2.88 14 22.6875 0.13 437. 173.9162 100.00 x x 5.62 15 23.4200 0.09 128. 18 3.7954 29.23 x x 0.78 1623.8750 0.18 96. 18 3.7241 21.99 x x 3.47 17 24.4900 0.12 72. 18 3.631916.54 x x 3.02 18 25.0125 0.18 26. 18 3.5572 5.95 x x 0.89 19 25.72750.18 20. 19 3.4599 4.64 x x 0.83 20 26.6250 0.18 114. 20 3.3453 26.21 xx 2.09 21 26.9725 0.09 246. 20 3.3030 56.43 x x 1.74 22 27.9675 0.07202. 21 3.1877 46.16 x x 1.32 23 28.5925 0.24 30. 22 3.1194 6.93 x x1.05 24 30.8400 0.07 196. 24 2.8970 44.87 x x 1.55 25 32.1275 0.18 38.24 2.7838 8.80 x x 1.82 26 32.6325 0.18 58. 25 2.7419 13.22 x x 2.04 2733.9250 0.18 174. 26 2.6403 39.89 x x 5.13 28 35.1000 0.18 17. 27 2.55463.85 x x 1.05 29 35.7950 0.24 32. 27 2.5065 7.44 x x 3.16 30 36.84000.36 37. 28 2.4378 8.52 x x 2.45 31 37.3975 0.15 35. 28 2.4027 7.97 x x1.07 32 37.8050 0.15 35. 28 2.3778 7.97 x x 1.15 33 38.5300 0.12 69. 292.3347 15.77 x x 1.15 Notes: Generator settings: 45 kV, 40 mA Cu alpha1,2 wave lengths 1.54060, 1.54439 Ang Step size, sample time 0.015 deg,0.20 s, 0.075 deg/s Monochromator used Divergence slit Automatic(irradiated sample length 12.5 mm) Peak angle range 2.007 - 40.002 degRange in D spacing 2.25207-43.9723 Ang Peak position criterion Top ofsmoothed data Cryst peak width range 0.00-2.00 deg Minim peaksignificance 0.75 Number of peaks in file 33 (alpha1: 33, amorphous: 0)Maximum intensity 437. cts, 2184.1 cps

EXAMPLE 5

2-(2-(3-(2-Phenyl)ethyl-7-propylbenz[4,5]isoxazol-6-yloxy)ethyl)indole-5-aceticAcid

Using the procedures in Example 1, steps F and G, the title compound wasprepared from methyl 2-(2-hydroxyethyl)indole-5-acetate and3-(2-phenyl)ethyl-7-(n-propyl)-6-hydroxybenz[4,5]isoxazole as a slightlytan solid.

EXAMPLE 6

2-(2-(4-phenoxy-2-propylphenoxy)ethyl)benzofuran-5-acetic Acid

Using the procedure from Example 1, steps F and G, the title compoundwas prepared from methyl 2-(2-hydroxyethyl)benzofuran-5-acetate and4-phenoxy-2-propylphenol as a colorless solid.

EXAMPLE 7

2-(2-(3-(2,2-Dimethylpropyl)-7-propylbenz[4,5]isoxazol-6-yloxy)ethyl)benzofuran-5-aceticAcid

Using the procedure from Example 1, steps F and G, the title compoundwas prepared from methyl 2-(2-hydroxyethyl)benzofuran-5-acetate and3-(2,2-dimethylpropyl)-7-propyl-6-hydroxybenz[4,5]isoxazole as acolorless oil.

EXAMPLE 8

2-(2-(3-Phenyl-7-propylbenz[4,5]isoxazol-6-yloxy)ethyl)benzofuran-5-aceticAcid

Using the procedure from Example 1, steps F and G, the title compoundwas prepared from methyl 2-(2-hydroxyethyl)benzofuran-5-acetate and3-phenyl-7-propyl-6-hydroxybenz[4,5]isoxazole as a colorless oil.

EXAMPLE 9

2-(2-(3-Phenyl-7-propylbenzofuran-6-yloxy)ethyl)-benzofuran-5-aceticAcid

Using the procedure from Example 1, steps F and G, the title compoundwas prepared from methyl 2-(2-hydroxyethyl)benzofuran-5-acetate and3-phenyl-6-hydroxy-7-propylbenzofuran as a colorless oil.

EXAMPLE 10

Step A

To a solution of methyl-6-hydroxy-1,2,3,4-tetrahydro-1-naphthoate (5 g)in THF (150 mL) was added dropwise over 1 hour a solution of pyridiniumtribromide (7.8 g in 150 mL THF). After the addition was complete thereaction was stirred for an additional 30 minutes. The reaction wasconcentrated to remove most of the THF and the residue diluted withethyl acetate and washed with water (×2), brine, dried over anhydroussodium sulfate and concentrated to yield a colorless solid. This solidwas recrystallized from toluene to give the desired monobromide.

Step B

A suspension of the monobromide (4 g), copper oxide (3 g), and4-t-butyltrimethylsiloxy-1-butyne (2.8 g) in pyridine (50 mL) was heatedat reflux 18hrs, then cooled to room temperature. The reaction wasfiltered through a pad of Celite and the filtrate partitioned betweenethyl acetate and water. The phases were separated and then the organicdried and concentrated to give a dark oil. The desired product waspurified by silica gel chromatography to give 2.3 g of an amber oil.

Step C

The TBS derivative (2.09 g) was dissolved in THF (10 mL) and chilled to0° C. and treated with 1M HCl (6 mL). After stirring 4 hours thereaction was diluted with ethylacetate and washed with water, 1M sodiumbicarbonate, water and brine. The solution was dried and concentrated togive an oil. The desired product was purified by silica gelchromatography to give an amber oil (1.3 g).

Step D

The alcohol (2.0 g), 2-propyl-4-phenoxyphenol (1.7 g),diisopropylazadicarboxylate (1.9 mL), triphenylphosphine (2.3 g) and THF(60 mL) were stirred at ambient temperature for 24 hrs thenconcentrated. The desired product was purified on silica gelchromatography to give cololess oil (1.2 g).

Step E

2-(2-(4-phenoxy-2-propylphenoxy)ethyl-4,5,6,7-tetrahydronaphtho[2,1-b]furan-7-carboxylicAcid Sodium Salt

The ester (1.05 g) was taken into aq. dioxane (5 mL) and treated with 5NNaOH (1.3 mL) and the resulting solution warmed to 60° C. for 4 hrs. Thereaction was acidified with 2N HCl and extracted with ethyl acetate.This solution was dried and concentrated. The residue was taken into drymethanol and treated with 0.5M sodium methoxide (1.0 eq) to give thedesired compound as a sodium salt.

EXAMPLE 11

2-(2-(3-phenyl-7-propylbenz[4,5]isoxazol-6-yloxy)ethyl)-4,5,6,7-tetrahydronaphtho[2,1-b]furan-7-carboxylicAcid

Using the procedure from Example 1, steps F and G, the title compoundwas prepared from methyl2-(2-hydroxyethyl)-4,5,6,7-tetrahydronaphtho[2,1-b]furan-7-carboxylateand 3-phenyl-7-propyl-6-hydroxybenz[4,5]isoxazole as a colorless oil.

EXAMPLE 12

2-(2-(3-(2,2-dimethylpropyl)-7-propylbenz[4,5]isoxazol-6-yloxy)ethyl)-4,5,6,7-tetrahydronaphtho[2,1-b]furan-7-carboxylicAcid

Using the procedure from Example 1, steps F and G, the title compoundwas prepared from methyl2-(2-hydroxyethyl)-4,5,6,7-tetrahydronaphtho[2,1-b]furan-7-carboxylateand 3-(2,2-dimethylpropyl)-7-(n-propyl)-6-hydroxybenz[4,5]isoxazole as acolorless oil.

EXAMPLE 13

Step A: Preparation of 4-(4-hydroxy)phenoxyphenylbenzoate

To a solution of 4,4′-oxydiphenol (2 g, 10 mmoL), pyridine (2.5 mL), anddichloromethane (35 mL) was added benzoyl chloride (1.2 mL) and theresulting solution was stirred overnight at ambient temperature. Thereaction was diluted with dichloromethane washed with water, 1M HCl,brine and dried over anhydrous sodium sulfate. After removal of solventthe desired produced was purified by silica gel chromatography(hexanes:ethyl acetate 7:3) to give a colorless oil. (2.26 g).

Step B: Preparation of 4-(3-propyl-4-hydroxy)phenoxyphenylbenzoate

Using the procedures from Example 4, steps A through C, the titlecompound was prepared from 4-(4-hydroxy)phenoxyphenylbenzoate.

Step C: Preparation of2-(2-(4-(4-benzoyloxy)phenoxy-2-propylphenoxy)ethyl)indole-5-acetic AcidMethyl Ester

Using the procedure from Example 1, step F, the title compound wasprepared from 2-(2-hydroxyethyl)indole-5-acetic Acid methyl ester and4-(3-propyl-4-hydroxy)phenoxyphenylbenzoate.

Step D: Preparation of2-(2-(4-(4-hydroxy)phenoxy-2-propylphenoxy)ethyl)indole-5-acetic AcidMethyl Ester

A solution of methanol (12 mL), water (6 mL), triethylamine (6 mL) and2-(2-(4-(4-benzoyloxy)phenoxy-2-propylphenoxy)ethyl)indole-5-acetic acidmethyl ester (760 mg) was warmed to reflux for 3 hours. The reaction wascooled and concentrated. The residue was taken into ethyl acetate andwashed with water, brine and dried over anhydrous sodium sulfate to givean amber oil. The desired compound was obtained by silica gelchromatography (hexanes:ethyl acetate) as a slightly amber colored oil(535 mg).

Step E: Preparation of2-(2-(4-(4-hydroxy)phenoxy-2-propylphenoxy)ethyl)indole-5-acetic Acid

A solution of2-(2-(4-(4-hydroxy)phenoxy-2-propylphenoxy)ethyl)indole-5-acetic acidmethyl ester (23 mg), dioxane (1 mL) and 5N NaOH (50 μL) was heated at60° C. for 1 hour. The solution was cooled and acidified with 2N HCl andextracted with ethyl acetate. The organic solution was dried overanhydrous sodium sulfate and concentrated to yield the desired productas a brown oil (18 mg).

¹HNMR (500 mHz, CD₃CN) 7.33 (s,1H), 4.23 (t,3H), 3.62 (s,2H), 3.19(t,2H), 2.45 (t,2H), 1.46-1.39 (m,2H), 0.90 (t,3H)

EXAMPLE 14

Step A: Preparation of Methyl2-(2-(4-(4-benzyloxy)phenoxy-2-propylphenoxy)ethyl)indole-5-acetate

To a solution of methyl2-(2-(4-(4-hydroxy)phenoxy-2-propylphenoxy)ethyl)indole-5-acetate,Example 13, Step D, (21 mg) in DMF (1 mL) was added sodium hydride (2mg, 60% in oil) and the reaction was stirred for 30 minutes. Benzylbromide (5.5 μL) was then added and the reaction was stirred for 12hours at room temperature. Water was added and the reaction extractedwith ethyl acetate, dried and concentrated. The desired compound waspurified by silica gel chromatography (hexanes:ethyl acetate 70:30)(17.4 mg).

Step B: Preparation of2-(2-(4-(4-benzyloxy)phenoxy-2-propylphenoxy)ethyl)indole-5-acetic Acid

A solution of methyl2-(2-(4-(4-benzyloxy)phenoxy-2-propylphenoxy)ethyl)indole-5-acetate (17mg), dioxane (1 mL) and 5N NaOH (31 μL) was warmed to 60° C. for 12hours. The reaction was cooled and acidified with 1M HCl and the productextracted with ethyl acetate to yield 8.8 mg.

¹HNMR (500 mHz, CDCl₃) 6.30 (s,1H), 5.05 (s,2H), 4.21 (t,3H), 3.74(s,2H), 3.25 (t,2H), 0.96 (t,3H).

EXAMPLE 15

2-(2-(4-(4-Fluorophenoxy)-2-propylphenoxy)ethyl)indole-5-acetic Acid

Step A: Preparation of 4-(4-fluorophenoxy)benzaldehyde

A solution of 4-fluorophenol (4.52 g, 40.29 mmol), 4-fluorobenzaldehyde(5.00 g, 40.29 mmol) and potassium carbonate (6.70 g, 48.35 mmol) inDMAC (40 mL) was refluxed for 12 h and cooled to room temperature. Waterwas added and the reaction mixture was extracted with ethyl acetate. Theorganic extract was washed with brine, dried over sodium sulfate,filtered and concentrated to afford an oil which was chromatographed onsilica gel (15% ethyl acetate/hexane) to afford the title compound.

Step B: Preparation of 4-(4-fluorophenoxy)phenol

A solution of 4-(4-fluorophenoxy)benzaldehyde (9.00 g, 41.63 mmol) inCHCl₃ (75 mL) was treated with m-chloroperbenzoic acid (46-85%, 15.80 g,52.00 mmol) and stirred for 3 h at room temperature. The reaction waswashed with sat. aq. NaHSO₃, sat. aq. NaHCO₃, and water. The organiclayer is concentrated and the residual oil taken up in MeOH (10 mL)containing a few drops of conc. HCL and stirred for 1 h at roomtemperature. The solvent is removed in vacuo and the resulting oil waschromatographed on silica gel (20% ethyl acetate/hexane) to afford thetitle compound.

Step C: Preparation of 4-(4-fluorophenoxy)phenyl Allyl Ether

A solution of 4-(4-fluorophenoxy)phenol (4.75 g, 23.30 mmol), potassiumcarbonate (4.17 g,. 30.30 mmol) and allyl bromide (2.22 mL, 25.60 mmol)in DMF (50 mL) was stirred for 5 h at 60° C. After cooling, the reactionmixture was neutralized with 1 N HCL and extracted with ethyl acetate.The organic extract was washed with brine, dried over sodium sulfate,filtered and concentrated to afford an oil which was chromatographed onsilica gel (15% ethyl acetate/hexane) to afford the title compound.

Step D: Preparation of 4-(4-fluorophenoxy)-2-allylphenol

4-(4-fluorophenoxy)phenyl allyl ether (4.00 g, 16.37 mmol) was taken upin 1,2-dichlorobenzene (50 mL) and refluxed for 48 h. After cooling, thesolvent was removed in vacuo and the resulting crude oil waschromatographed on silica gel (15% ethyl acetate/hexane) to afford thetitle compound.

Step E: Preparation of 4-(4-fluorophenoxy)-2-propylphenol

A solution of 4-(4-fluorophenoxy)-2-allylphenol (2.30 g, 9.42 mmol) and5% Pd/C (0.90 g) in ethyl acetate (30 mL) was stirred under H₂atmosphere for 3 h at room temperature. The reaction mixture wasfiltered through a short pad of silica gel and concentrated in vacuo toafford the title compound which was used as is.

Step F: Preparation of2-(2-(4-(4-fluorophenoxy)-2-propylphenoxy)ethyl)-indole-5-acetate

A solution of 4-(4-fluorophenoxy)-2-propylphenol (0.17 g, 0.70 mmol),2-(2-hydroxyethyl)indole-5-acetate (0.15 g,. 0.64 mmol) andtriphenylphosphine (0.18 g, 0.67 mmol) in THF (3 mL) was treated withdiisopropylazodicarboxylate (0.13 mL, 0.67 mmol) and stirred 16 h atroom temperature. The reaction mixture was concentrated andchromatographed on silica gel (15% ethyl acetate/hexane) to afford thetitle compound.

Step G: Preparation of2-(2-(4-(4-fluorophenoxy)-2-propylphenoxy)ethyl)-indole-5-acetic Acid

A solution of2-(2-(4-(4-fluorophenoxy)-2-propylphenoxy)-ethyl)-indole-5-acetate (mg,mmol) in MeOH (mL) and LiOH (mL) was heated at reflux for 3 hours. Themixture was acidified to pH 6 with 1 N HCL and extracted with ethylacetate. The organic layer was dried over sodium sulfate, filtered andconcentrated to afford the title compound.

¹NMR (CDCl₃, ppm) δ8.38 (broad s, 1H), 7.46 (s, 1H), 7.25 (d,1H),6.75-7.10 (m, 7H), 6.30 (s, 1H), 4.23 (t, 2H), 3.73 (s, 2H), 3.27(t, 2H), 2.64 (t, 2H), 1.65 (m, 2H), 0.98 (t, 3H)

EXAMPLE 16

2-(2-(4-(4-Trifluoromethylphenoxy)-2-propylphenox=)-ethyl)indole-5-aceticAcid

Step A: Preparation of 4-(4-trifluoromethylphenoxy)-2-propylphenol

Using the procedures in Example 15, steps A through E, and substituting4-trifluoromethylphenol for 4-fluorophenol in step A, the title compoundwas prepared.

Step B: Preparation of2-(2-(4-(4-trifluoromethylphenoxy)-2-propylphenoxy)ethyl)indole-5-aceticAcid

Using the procedures in Example 15, steps F and G, the title compoundwas prepared from methyl 2-(2-hydroxyethyl)indole-5-acetate and4-(4-trifluoromethylphenoxy)-2-propylphenol.

¹NMR (CDCl₃, ppm) δ8.39 (broad s, 1H), 7.46 (s, 1H), 7.22-7.43 (m, 2H),7.06 (d, 2H), 6.93 (d, 2H), 6.89 (s, 1H), 6.81 (s, 1H), 6.30 (s, 1H),4.23 (t, 2H), 3.73 (s, 2H), 3.25 (t, 2H), 2.63 (t, 2H), 1.65 (m, 2H),0.99 (t, 3H)

EXAMPLE 17

2-(2-(4-(4-Chlorophenoxy)-2-propylphenoxy)ethyl)indole-5-acetic Acid

Step A: Preparation of 4-(4-chlorophenoxy)-2-propylphenol

Using the procedures in Example 15, steps A through E, and substituting4-chlorophenol for 4-fluorophenol in step A, the title compound wasprepared.

Step B: 2-(2-(4-(4-Chlorophenoxy)-2-propylphenoxy)ethyl)indole-5-aceticAcid

Using the procedures in Example 15, steps F and G, the title compoundwas prepared from methyl 2-(2-hydroxyethyl)indole-5-acetate and4-(4-chlorophenoxy)-2-propylphenol.

¹NMR (CDCl₃, ppm) δ8.37(broad s, 1H), 7.46 (s, 1H), 7.20-7.28 (m, 2H),7.06 (d, 1H), 6.80-6.88 (m, 5H), 6.30 (s, 1H), 4.23 (t, 2H), 3.73 (s,2H), 3.26 (t, 2H), 2.63 (t, 2H), 1.65 (m, 2H), 0.99 (t, 3H)

EXAMPLE 18

2-(2-(5-(4-Propyl-N-neopentyl)indolyloxy)ethyl)indole-5-acetic Acid

Step A: Preparation of 5-allyloxyindole

5-Hydroxyindole (1.00 g, 7.29 mmol) and potassium carbonate (1.38 g,9.94 mmol) were taken up in 20 mL of dimethylformamide (DMF) and stirredat 60° C. for 0.5 hours. Allyl bromide (0.57 mL, 6.62 mmol) was addedand the reaction was stirred for an additional 18 hours then cooled anddiluted with ethyl acetate. The organic layer was washed with water,brine, dried over magnesium sulfate, filtered, concentrated in vacuo,and the crude residue was purified by flash chromatography on silica gel(10% ethyl acetate/hexane) to provide the title compound.

Step B: Preparation of 5-allyloxy-N-neopentylindole

To a solution of sodium hydride (60%, 254 mg, 6.35 mmol) in 15 mLtetrahydrofuran (THF) was added 5-allyloxyindole (Step A; 1.0 g, 5.77mmol) in 5 mL THF and the mixture was stirred for 1 hour at ambienttemperature. Neopentyl iodide (0.69 mL, 6.35 mmol) was added and thereaction heated to reflux for 21 hours. After cooling, the reaction wasquenched with saturated aqueous ammonium chloride and extracted withethyl acetate. The organic layer was washed with water, brine, driedover magnesium sulfate, filtered, concentrated in vacuo, and the cruderesidue purified by flash chromatography on silica gel (15% ethylacetate/hexane) to provide the title compound.

Step C: Preparation of 4-allyl-5-hydroxy-N-neopentylindole

5-Allyloxy-N-neopentylindole (Step B; 1.4 g, 4.93 mmol) was refluxed in20 mL 1,2-dichlorobenzene for 4 hours. The reaction mixture was cooledand immediately purified by flash chromatography on silica gel (gradientelution: hexane then 10% ethyl acetate/hexane) to provide the titlecompound.

Step D: Preparation of 5-hydroxy-4-propyl-N-neopentylindole

4-Allyl-5-hydroxy-N-neopentylindole (Step C; 1.0 g, 3.54 mmol) was takenup in 25 mL ethyl acetate and hydrogenated (1 atm) at ambienttemperature using 5% palladium on charcoal (40 mg) for 2 hours. Thereaction was filtered through celite and concentrated in vacuo toprovide the title compound which was used without further purification.

Step E: Preparation of2-(2-(5-(4-propyl-N-neopentyl)indolyloxy)ethyl)indole-5-acetic Acid

Using the procedures in Example 15, steps E and F, the title compoundwas prepared from 5-hydroxy-4-propyl-N-neopentylindole and2-(2-hydroxyethyl)indole-5-acetate.

¹NMR (CDCl₃, ppm) 8.68 (broad s, 1H), 7.45 (s, 1H), 7.24 (d, 1H),7.00-7.14 (m, 2H), 6.88 (d, 1H), 6.45 (d, 1H), 6.29 (s, 1H), 4.27 (t,2H), 3.83 (s, 2H), 3.71 (s, 2H), 3.25 (t, 2H), 2.90 (t, 2H), 1.73 (m,2H), 1.02 (t, 3H), 1.00 (s, 9H)

EXAMPLE 19

2-(2-(5-(4-propyl-N-neophyl-indolyloxy)ethyl)-indole-5-acetic Acid

Step A: Preparation of 5-hydroxy-4-propyl-N-neophylindole

Using the Procedures in Example 18, steps A through E, and substitutingneophyl chloride for neopentyl iodide in step B, the title compound wasprepared.

Step B: Preparation of2-(2-(5-(4-propyl-N-neophyl)indolyloxy)ethyl)-indole-5-acetic Acid

Using the procedures in Example 15, steps E and F, the title compoundwas prepared from 5-hydroxy-4-propyl-N-neophyllindole and2-(2-hydroxyethyl)indole-5-acetate.

¹NMR (CDCl₃, ppm) δδ8.65 (broad s, 1H), 7.46 (s, 1H), 7.33 (d, 2H), 7.05(dd, 1H), 6.95 (dd, 1H), 6.81 (dd, 1H), 6.52 (d, 1H), 6.30 (dd, 2H),4.27 (t, 2H), 4.17 (s, 2H), 3.70 (s, 2H), 3.23 (t, 2H), 2.88 (t, 2H),1.22 (m, 2H), 1.40 (s, 6H), 0.98 (t, 3H)

EXAMPLE 20

2-(2-((4-Benz[4,5]isoxazol-3-yl)-2-propylphenoxy)ethyl)indole-5-aceticAcid

Step A: Preparation of 4-hydroxy-5-propyl-2′-fluorobenzophenone

A 0° C. suspension of 2-fluorobenzoyl chloride (1.3 mL, 11.03 mmol) in15 mL of 1,2-dichloroethane was treated with aluminum chloride (1.0 g,7.35 mmol). The suspension was vigorously stirred for 15 minutes. Asolution of 2-propylphenol (1.0 g, 7.35 mmol) in 5 mL of1,2-dichloro-ethane was added dropwise. The mixture was allowed to stirand gradually warm to 25° C. over 6 hours. The mixture was slowly addedto a stirred mixture of water and methylene chloride. The organic phasewas dried over magnesium sulfate, filtered and concentrated to a solid.The crude residue was purified via flash chromatography on silica gel(15% ethyl acetate/hexane eluent) to afforded the title compound.

Step B: Preparation of 4-hydroxy-5-propyl-2′-fluorobenzophenone Oxime

A solution of 4-hydroxy-5-propyl-2′-fluorobenzophenone (Step A; 1.35 g,5.23 mmol) in 15 mL of pyridine was treated with hydroxylaminehydrochloride (1.82 g, 26.15 mmol). The mixture was refluxed for 24hours, cooled and the pyridine removed in vacuo. The residue was takenup in ethyl acetate and washed with 1N hydrochloric acid, water, brine,dried over MgSO₄, filtered and concentrated in vacuo. The crude residuewas purified via flash chromatography on silica gel (20% ethylacetate/hexane eluent) to yield the title compound.

¹NMR (CDCl₃, ppm) δ0.96 (t, 3H), 1.22 (m, 2H), 1.56 (t, 2H), 6.82 (d,1H), 7.13-7.57 (m, 7H); ESI: MS m/e=259 (M+1)

Step C: Preparation of 4-(1,2-benz[4,5]isoxazol-3-yl)-2-propylphenol

Sodium hydride (60%; 160 mg, 4.0 mmol) was taken up in 7 mL ofdimethylformamide (DMF) and 7 mL of benzene.4-hydroxy-5-propyl-2′-fluorobenzophenone oxime (Step B; 517 mg, 2.0mmol) was added in 3 mL of DMF and 3 mL of benzene and the reactionstirred at 50° C. for 2 hours. After cooling, the reaction was quenchedwith saturated aqueous ammonium chloride and extracted with ethylacetate. The organic phase was washed with water, brine, dried (MgSO₄),filtered and concentrated in vacuo. The crude residue was purified byflash chromatography on silica gel (10% ethyl acetate/hexane eluent) toafford the title compound.

Step D: Preparation of2-(2-((4-benz[4,5]isoxazol-3-yl)-2-propylphenoxy)ethyl)-indole-5-aceticAcid

Using the procedures in Example 15, steps E and F, the title compoundwas prepared from 4-(1,2-benzisoxazol-3-yl)-2-propylphenol and2-(2-hydroxyethyl)indole-5-acetate.

¹NMR (CDCl₃, ppm) δ8.32 (broad s, 1H), 7.92 (d, 1H), 7.76-7.81 (m, 2H),7.55-7.65 (m, 2H), 7.46 (s, 1H), 7.35-7.41 (td, 1H), 7.07 (d, 1H), 7.02(d, 1H) 6.33 (s, 1H), 4.36 (t, 2H), 3.72 (s, 2H), 3.68 (s, 3H), 3.31 (t,2H), 2.75 (t, 2H), 1.22 (m, 2H), 1.03 (t, 3H)

BIOLOGICAL ASSAYS

I. White Adipose Tissue in vitro Assay

The ability of compounds of the present invention to enhance the insulinactivation of ¹⁴C-glucose incorporation into glycogen in white adiposetissue (WAT) was determined by the following assay.

This assay measures the efficacy of the instant compounds to enhance theinsulin activation of ¹⁴C-glucose incorporation into glycogen in whiteadipose tissue (WAT) in a 5 hour completely in vitro system. Allprocedures are performed in medium 199 containing 1% bovine serumalbumen, 5 mM HEPES, and antibiotic (100 units/ml penicillin, 100 μg/mlstreptomycin sulfate, 0.25 μg/ml amphotericin B), hereafter calledculture medium. Epididymol fat pads are minced with scissors into smallfragments, approximately 1 mm in diameter. Minced WAT fragments (100 mg)are incubated in a total volume of 0.9 ml culture medium containing 1mU/ml insulin and test compound in tissue culture incubator at 37° C.with 5% CO₂ with orbital shaking for 3 hours. ¹⁴C-labeled glucose isadded and incubation continued for 2 hours. Tubes are centrifuged at lowspeed, infranatant is removed and 1 M NaOH is added. Incubation ofalkali-treated WAT for 10 minutes at 60° C. solubilizes tissue.Resulting tissue hydrolyzate is applied to Whatman filter paper stripswhich are then rinsed in 66% ethanol followed by 100% acetone whichremoves unincorporated ¹⁴C-glucose from bound ¹⁴C-glycogen. The driedpaper is then incubated in solution of amyloglucosidase to cleaveglycogen into glucose. Scintillation fluid is added and samples arecounted for ¹⁴C activity. Test compounds that resulted in ¹⁴C activitysubstantially above incubations with insulin alone are considered activeinsulin-enhancing agents. Active compounds were titrated to determinethe compound concentration which resulted in 50% of maximum enhancementof insulin activation and were termed EC₅₀ values. EC₅₀ values for theinstant compounds were found to be 50 μM or less, preferably 5.0 to0.0001 μM or less.

II. PPAR Receptor Binding Assay

Compounds of the instant invention which are useful for the abovediscussed treatments can be identified and/or characterized by employingthe PPAR δ, and γ binding assays. The assays are useful in predicting orquantitating in vivo effects having to do with the control or modulationof glucose, free fatty acid, triglyceride, insulin or cholesterol. Toevaluate IC₅₀ or EC₅₀, values the compounds were titrated in theappropriate assay using different concentrations of the compound to betested. To obtain the appropriate values (%Inhibition-IC₅₀, or%Activation-EC₅₀), the data resulting from the assays were then analyzedby determining the best fit of a 4 parameter function to the data usingthe Levenberg-Marquardt non-linear fitting algorithm in Kaleidagraph(Synergy Software, Reading, Pa.). The human nuclear receptor cDNA forPPARδ (hPPARδ) has been cloned from a human osteosarcoma cell cDNAlibrary and is fully described in A. Schmidt et al., MolecularEndocrinology, 6:1634-1641 (1992), herein incorporated by reference inits entirety. See A. Elbrecht et al., Biochem. and Biophy. Res. Comm.224:431-437 (1996) and T. Sher et al., Biochem. 32:5598-5604 (1993) fora description of the human nuclear receptor gene PPARγ and α.

The hPPARδ binding assay comprises the steps of:

(a) preparing multiple test samples by incubating separate aliquots ofthe receptor hPPARδ with a test compound in TEGM containing 5-10% COS-1cell cytoplasmic lysate and 2.5 nM labeled ([³H₂]Compound D, 17Ci/mmole) for a minimum of 12 hours, and preferably for about 16 hours,at 4° C., wherein the concentration of the test compound in each testsample is different, and preparing a control sample by incubating afurther separate aliquot of the receptor hPPARδ under the sameconditions but without the test compound; then

(b) removing unbound ligand by adding dextran/gelatin-coated charcoal toeach sample while maintaining the samples at 4° C. and allowing at least10 minutes to pass, then

(c) subjecting each of the test samples and the control sample from step(b) to centrifugation at 4° C. until the charcoal is pelleted; then

(d) counting a portion of the supernatant fraction of each of the testsamples and the control sample from step (c) in a liquid scintillationcounter and analyzing the results to determine the IC₅₀ of the testcompound.

In the hPPARδ binding assay, preferably at least four test samples ofvarying concentrations of a single test compound are prepared in orderto determine the IC₅₀.

Particular terms and abbreviations used herein are defined as follows:gst is glutathione-S-transferase; EDTA is ethylenediamine-tetraaceticacid; HEPES is N-[2-hydroxyethyl]-piperazine-N′-[2-ethanesulfonic acid];FCS is fetal calf serum; Lipofectamine is a 3:1 (w/w) liposomeformulation of the polycationic lipid2,3-dioleyloxy-N-[2(spermine-carboxamido)ethyl]-N,N-dimethyl-1-propanaminium-trifluoroacetateand the neutral lipid dioleoyl phosphatidylethanolamine in water; G418is geneticin; MEM is Minimum Essential Medium; Opti MEM 1 Reduced-SerumMedium is an aqueous composition containing HEPES buffer, 2400 mg/Lsodium bicarbonate, hypoxanthine, thymidine, sodium pyruvate,L-glutamine, trace elements, growth factors, and phenol red reduced to1.1 mg/L; Luciferase Assay Reagent (in reconstituted form) is an aqueouscomposition containing 20 mM tricine, 1.07 mM (MgCO₃)₄Mg(OH)₂.5H₂O, 2.67mM MgSO₄, 0.1 mM EDTA, 33.3 mM DTT, 270 μM coenzyme A, 470 μM luciferin,530 μM ATP, having a final pH of 7.8.

AD-5075 has the following structure:

Opti MEM 1 Reduced-Serum Medium, alpha MEM, G418, and Lipofectamine arecommercially available from GibcoBRL Life Technologies, Gaithersburg,Md. Alpha MEM is an aqueous composition having the following components:

mg/L Component: Inorganic Salts CaCl₂ (anhyd.) 200.00 CaCl₂ .2H₂O — KCl400.00 MgSO₄ (anhyd.) 97.67 MgSO₄.7H₂O — NaCl 6800.00 NaHCO₃ 2200.00NaH₂PO₄.H₂O 140.00 NaH₂PO₄.2H₂O — Other Components: D-Glucose 1000.00Lipoic Acid 0.20 Phenol Red 10.00 Sodium Pyruvate 110.00 Amino Acids:L-Alanine 25.00 L-Arginine.HCl 126.00 L-Asparagine.H₂O 50.00 L-AsparticAcid 30.00 L-Cystine — L-Cystine.2HCl 31.00 L-Cysteine HCl — L-CysteineHCl.H₂O 100.00 L-Glutamic Acid 75.00 L-Glutamine 292.00L-Alanyl-L-Glutamine — Glycine 50.00 L-Histidine HCl.H₂O 42.00L-Isoleucine 52.00 L-Leucine 52.00 L-Lysine.HCl 73.00 L-Methionine 15.00L-Phenylalanine 32.00 L-Proline 40.00 L-Serine 25.00 L-Threonine 48.00L-Tryptophan 10.00 L-Tyrosine — L-Tyrosine (disodium salt) 52.00L-Valine 46.00 Vitamins: L-Ascorbic acid 50.00 Biotin 0.10 D-CaPantothenate 1.00 Choline Chloride 1.00 Folic acid 1.00 i-Inositol 2.00Niacinamide 1.00 Pyridoxal HCl 1.00 Riboflavin 0.10 Thiamine HCl 1.00Vitamin B₁₂ 1.40 Ribonucleosides Adenosine 10.00 Cytidine 10.00Guanosine 10.00 Uridine 10.00 Deoxyribonucleosides 2′ Deoxyadenosine10.00 2′ Deoxycytidine HCl 11.00 2′ Deoxyguanosine 10.00 Thymidine 10.00

The instant compounds, which are useful for treating the above discusseddisease states, will preferably have IC₅₀ values at one, two or all ofthe PPAR (PPARγ, PPARδ or PPARα) receptor sites of equal to or less than10 μM in the binding assay, preferably, an IC₅₀ of 100 nM in the bindingassay, and more preferably, the instant compounds have an IC₅₀ equal toor less than 50 nM in the binding assay. Most preferably, the instantcompounds have an IC₅₀ equal to or less than 10 nM in the binding assay.

PPAR Receptor Binding Assay

A. Preparation of Human PPARγ2 and δ

Human PPARγ2 and PPARδ, independently, were prepared as gst-fusionproteins in E. coli. The full length human cDNA for PPARγ2 and PPARδwere subcloned into the PGEX-2T and PGEX-KT, respectively, expressionvector (Pharmacia). E. coli containing the plasmid were grown, induced,and then harvested by centrifugation. The resuspended pellet was brokenin a French press and debris was removed by centrifugation at 12,000×g.Receptors were purified from the supernatant by affinity chromatographyon glutathione sepharose. After application to the column, and 1 wash,receptor was eluted with glutathione. Glycerol was added to stabilizethe receptor and aliquots were frozen at −80° C. for later use.

B. [³H]AD-5075 and Example 11 Displacement Assay for PPARγ2 and PPARδ,respectively

For each assay, an aliquot of receptor (1:1000-1:3000 dilution) wasincubated in TEGM (10 mM Tris, pH 7.2, 1 mM EDTA, 10% glycerol, 7 μl/100ml β-mercaptoethanol, 10 mM Na molybdate, 1 mM dithiothreitol, 5 μg/mlaprotinin, 2 μg/ml leupeptin, 2 μg/ml benzamide and 0.5 mM PMSF)containing 5-10% COS-1 cell cytoplasmic lysate and 10 nM labeledthiazolidinedione ([³H₂]AD-5075, 21 Ci/mmole), ±test compound compound,[³H₂]Example 11, 17 Ci/mmole), ±test compound, respectively. Assays wereincubated for ˜16 h at 4° C. in a final volume of 300 μl. Unbound ligandwas removed by addition of 200 μl dextran/gelatin-coated charcoal, onice, for ˜10 minutes. After centrifugation at 3000 rpm for 10 min at 4°C., 200 μl of the supernatant fraction was counted in a liquidscintillation counter. In this assay the K_(D) for AD-5075 and Example11 is ≈1 nM, respectively.

III. In Vivo Studies

Methods

db/db Mice are obese, highly insulin resistant animals. The db locus hasbeen shown to code for the leptin receptor. These animals aresubstantially hypertriglyceridemic and hyperglycemic.

Male db/db mice (10-11 week old C57Bl/KFJ, Jackson Labs, Bar Harbor,Me.) were housed 5/cage and allowed ad lib. access to ground Purinarodent chow and water. The animals, and their food, were weighed every 2days and were dosed daily by gavage with vehicle (0.5%carboxymethylcellulose)±test compound at the indicated dose. Drugsuspensions were prepared daily. Plasma glucose, Cholesterol andtriglyceride concentrations were determined from blood obtained by tailbleeds at 3-5 day intervals during the study period. Glucose,cholesterol and triglyceride, determinations were performed on aBoehringer Mannheim Hitachi 911 automatic analyzer (Boehringer Mannheim,Indianapolis, Ind.) using heparinized plasma diluted 1:5, or 1:6 (v/v)with normal saline. Lean animals were age-matched heterozygous micemaintained in the same manner. The instant compounds were found to lowertriglyceride and glucose levels at a dose of about 100 mg/kg, preferablya dose of about 10-50 mg/kg, when administered by oral gavage daily fora period of at least 5 days.

Lipoprotein analysis was performed on either serum, or EDTA treatedplasma obtained by heart puncture from anesthetized animals at the endof the study. Apolipoprotein concentrations were determined by ELISA,and cholesterol particles were analyzed by FPLC, precipitation, orultracentrifugation. Total liver RNA was prepared from tissue that hadbeen frozen on liquid nitrogen at the time of euthanasia. ApolipoproteinmRNA was analyzed on Northern Blots using specific probes for mouse orrat proteins.

What is claimed is:
 1. A compound having the formula I or Ia:

or a pharmaceutically acceptable salt thereof, wherein: A is a single ordouble bonded carbon or a single or double bond; R¹ is selected from agroup consisting of: H, C₁₋₁₅ alkyl, C₂₋₁₅ alkenyl, C₂₋₁₅ alkynyl andC₃₋₁₀ cycloalkyl, said alkyl, alkenyl, alkynyl, and cycloalkyloptionally substituted with 1 to 3 groups of R^(a); R² is selected froma group consisting of: H, C₁₋₁₅ alkyl, C₂₋₁₅ alkenyl, OR³, CO₂alkyl,COalkyl, OH, —OC(O)R³, C₂₋₁₅ alkynyl, C₅₋₁₀ aryl, and C₅₋₁₀ heteroaryl,wherein said heteroaryl is selected from the group consisting oftetrazole, benzothiophene, and benzofuran, said alkyl, alkenyl, alkynyl,aryl and heteroaryl optionally substituted with 1 to 3 groups of R^(a);R³ is selected from a group consisting of: H, NHR¹, NHacyl, C₁₋₁₅ alkyl,C₂₋₁₅ alkenyl, C₁₋₁₅ alkoxy, CO₂alkyl, OH, C₂₋₁₅ alkynyl, C₅₋₁₀ aryl,and C₅₋₁₀ heteroaryl, wherein said heteroaryl is selected from the groupconsisting of tetrazole, benzothiophene, and benzofuran, said alkyl,alkenyl, alkynyl, aryl and heteroaryl optionally substituted with 1 to 3groups of R^(a); R⁴ is selected from the group consisting of: R², —D—R⁵and

R⁵ is selected from the group consisting of: C₅₋₁₀ aryl and C₅₋₁₀heteroaryl, wherein said heteroaryl is selected from the groupconsisting of tetrazole, benzothiophene, and benzofuran, said aryl andheteroaryl optionally substituted with 1 to 3 groups of R^(a); W is—CR⁶R⁷—, or

R⁸ is selected from the group consisting of CR⁶R⁷, O, NR⁶, and S(O)_(P);R⁶ and R⁷ are independently selected from the group consisting of H andC₁₋₆ alkyl; B is a 5 membered heterocycle containing 1 double bond and 1heteroatom selected from the group consisting of O and S, wherein saidheterocycle and the aromatic ring to which it is fused representbenzothiophene or benzofuran, the heterocycle being optionallyunsubstituted or substituted with 1 to 3 groups of R^(a); D is selectedfrom the group consisting of: O, S(O)p and NR¹; X¹ and X² areindependently selected from a group consisting of: H, OH, C₁₋₁₅ alkyl,C₂₋₁₅ alkenyl, C₂₋₁₅ alkynyl, halo, OR³, C₅₋₁₀ aryl, C₅₋₁₀ aralkyl,C₅₋₁₀ heteroaryl and C₂₋₁₀ acyl, wherein said heteroaryl is selectedfrom the group consisting of tetrazole, benzothiophene, and benzofuran,said alkyl, alkenyl, alkynyl, aryl and heteroaryl optionally substitutedwith 1 to 3 groups of R^(a); R^(a) represents a member selected from thegroup consisting of: halo, aryl, heteroaryl, CF₃, OCF₃, CN, NO₂, R³,OR³; SR³, S(O)R³, SO₂R³, NR³R³, NR³COR³, NR³CO₂R³, NR³CON(R³)₂,NR³SO₂R³, COR³, CO₂R³, CON(R³)₂, SO₂N(R³)₂, and OCON(R³)₂, wherein saidheteroaryl is selected from the group consisting of tetrazole,benzothiophene, and benzofuran and said aryl and heteroaryl areoptionally substituted with 1 to 3 groups of halo or C1-6 alkyl; Y isselected from the group consisting of: S, —CH₂—, CO, and O with theproviso that if A is a single or double bonded carbon or a single bond,Y is —CH₂— or CO; Y² is selected from the group consisting of: O,N(C₁₋₁₅) alkyl, N(CO₂)alkyl, N—Oalkyl, N—Oacyl and N—OH, with theproviso that if Y² is O and R³ is CH₃ then n is 2; Y¹ is selected fromthe group consisting of: O, NH, S(O)_(p) and CH₂; Z is selected from thegroup consisting of: CO₂R³, CONHSO₂Me, CONH₂ and 5-(1H-tetrazole); or(Z—W)_(t) or (Z—W)_(v) together with X¹ can form a 5 or 6 membered ring,said ring being a carbocycle, optionally substituted with 1 to 3 groupsof R^(a); in the case where (Z—W)_(t) is used v is 0 or 1; in the casewhere (Z—W)_(v) is used t is 0 or 1; t and v are independently 0 or 1such that t+v=1; n is 2-4; p is 0-2; and at least one heteroarylsubstituent or the combination of B and the aromatic ring to which B isfused or the bicyclic structure on the left side of formula 1 or 1a isbenzofuran.
 2. A compound represented by formula I or Ia:

or a pharmaceutically acceptable salt thereof, wherein: A represents asingle or double bonded carbon, or a direct single or double bond; Yrepresents a member selected from the group consisting of: S, —CH₂—,—C(O)—, and —O—, with the proviso that if A represents a single ordouble bonded carbon or a single bond, Y is —CH₂— or —C(O)—; one of tand v is zero and the other is 1; W is

 and Z is selected from the group consisting of: CO₂R^(3′), CONHSO₂C₁₋₆alkyl, CONH₂ and 5-(1H-tetrazolyl); or in the alternative, one of(Z—W)_(t) and (Z—W)_(v) is taken in combination with X¹ to represent a 5or 6 membered fused ring, said ring being a carbocycle, optionallysubstituted with 1 to 3 R^(a) groups; when (Z—W)_(t) is taken incombination with X¹, v is 0 or 1, and when (Z—W)_(v) is taken incombination with X¹, t is 0 or 1; X¹ and X² are independently selectedfrom a group consisting of: H, OH, C₁₋₁₅ alkyl, C₂₋₁₅ alkenyl, C₂₋₁₅alkynyl, halo, C₅₋₁₀ aryl, C₅₋₁₀ heteroaryl, C₂₋₁₀ acyl, C₁₋₅ alkoxy,C₅₋₁₀ aryloxy, C₂₋₁₅ alkenyloxy, C₂₋₁₅ alkynyloxy, heteroaryloxy, andC₂₋₁₀ acyloxy, wherein said heteroaryl is selected from the groupconsisting of tetrazole, benzothiophene, and benzofuran, said alkyl,alkenyl, alkynyl, aryl, acyl and heteroaryl, and the alkyl, alkenyl,alkynyl, aryl, acyl and heteroaryl portions of alkoxy, aryloxy,alkenyloxy, alkynyloxy, heteroaryloxy and acyloxy being optionallysubstituted with 1 to 3 R^(a) groups; n is 2, 3 or 4; Y¹ represents O,NH, CH₂ or S(O)_(p); p is 0, 1 or 2; B represents a 5 or 6 memberedfused ring containing 0 to 2 double bonds, and optionally containing 1heteroatom selected from the group consisting of O and S, with theproviso that when B is a heterocycle, said heterocycle and the aromaticring to which it is fused represent benzothiophene, or benzofuran, saidring being optionally substituted with 1 to 3 R^(a) groups; R¹ isselected from a group consisting of: H, C₁₋₁₅ alkyl, C₂₋₁₅ alkenyl andC₂₋₁₅ alkynyl, said alkyl, alkenyl and alkynyl being optionallysubstituted with 1 to 3 R^(a) groups; R² is selected from a groupconsisting of: H, OH, C₁₋₁₅ alkyl, C₂₋₁₅ alkenyl, C₂₋₁₅ alkynyl, C₅₋₁₀aryl, C₅₋₁₀ heteroaryl, —C(O)C₁₋₁₅ alkyl, CO₂C₁₋₆ alkyl, —OC(O)R^(3′),C₁₋₆ alkoxy, C₅₋₁₀ aryloxy, C₂₋₁₅ alkenyloxy, C₂₋₁₅ alkynyloxy,heteroaryloxy and C₂₋₁₀ acyloxy, wherein said heteroaryl and theheteroaryl portion of heteroaryloxy are selected from the groupconsisting of tetrazole, benzothiophene, and benzofuran, said alkyl,alkenyl, alkynyl, aryl and heteroaryl, and the alkyl, aryl, alkenyl,alkynyl, heteroaryl and acyl portions of alkoxy, aryloxy, alkenyloxy,alkynyloxy, heteroaryloxy and acyloxy being optionally substituted with1 to 3 R^(a) groups; R³ is selected from a group consisting of: H, OH,NHR¹, NHacyl, C₁₋₅ alkyl, C₂₋₁₅ alkenyl, C₁₋₁₅ alkoxy, CO₂alkyl, C₂₋₁₅alkynyl, C₅₋₁₀ aryl, and C₅₋₁₀ heteroaryl wherein said heteroaryl isselected from the group consisting of tetrazole, benzothiophene, andbenzofuran, said alkyl, alkenyl, alkynyl, aryl and heteroaryl optionallysubstituted with 1 to 3 R^(a) groups; each R^(a) independentlyrepresents a member selected from the group consisting of: R^(3′), halo,CF₃, OCF₃, CN, NO₂, OR^(3′), S(O)_(p)—R^(3′); N(R^(3′))₂,NR^(3′)COR^(3′), NR^(3′)CO₂R^(3′), NR^(3′)CON(R³)₂, NR^(3′)SO₂R^(3′),C(O)R^(3′), CO₂R^(3′), CON(R^(3′))₂, SO₂N(R^(3′))₂, and OCON(R^(3′))₂,and when R^(3′) is present and represents alkyl, alkenyl, alkynyl, arylor heteroaryl, said alkyl, alkenyl, alkynyl, aryl or heteroaryl group isoptionally substituted with 1 to 3 halo, hydroxy, C₁₋₃ alkoxy, carboxyor amino groups, and when at least two R^(a) groups are present, theymay also be taken in combination with any intervening atoms to representa 4-6 membered ring, said ring containing no heteroatoms, and said ringbeing optionally interrupted by 1-2 —C(O)— groups, and optionallysubstituted with 1-3 halo, hydroxy, C₁₋₆ alkyl or amino groups; R^(3′)represents H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl or heteroarylwherein said heteroaryl is selected from the group consisting oftetrazole, benzothiophene, and benzofuran; R⁴ represents R², —D—R⁵ or

D is selected from O, S(O)p, NR¹ and CR⁶R⁷; R⁵ is selected from thegroup consisting of: C₅₋₁₀ aryl and C₅₋₁₀ heteroaryl, wherein saidheteroaryl is selected from the group consisting of tetrazole,benzothiophene, and benzofuran, said aryl and heteroaryl beingoptionally substituted with 1 to 3 R^(a) groups; Y² is selected from thegroup consisting of: O, N(C₁₋₁₅) alkyl, N(CO₂)alkyl, N—Oalkyl, N—Oacyland N—OH, with the proviso that if Y² is O and R³ is CH₃ then n is 2; R⁸is optional and is selected from the group consisting of CR⁶R⁷, O, NR⁶and S(O)_(P), R⁶ and R⁷ are independently selected from H and C₁₋₆alkyl; and at least one heteroaryl substituent or the combination of Band the aromatic ring to which B is fused or the bicyclic structure onthe left side of formula 1 or 1a is benzofuran.
 3. A compound of claim 1where X¹ and X² are independently H or halo.
 4. A compound of claim 1where Y is O.
 5. A compound of claim 1 where Y is S(O)_(p), wherein p is0-2.
 6. A compound of claim 1 where Y is —CH₂—.
 7. A compound of claim 1where Y is —CO—.
 8. A compound of claim 1 where A is a single or doublebonded carbon.
 9. A compound of claim 1 where A is a single or doublebond.
 10. A compound of claim 1 having the formula I where B is a 5membered heterocycle, wherein said heterocycle and the aromatic ring towhich it is fused represent benzothiophene, or benzofuran, theheterocycle being optionally unsubstituted or substituted with 1 to 3groups of R^(a).
 11. A compound of claim 1 where R⁴ is selected from thegroup consisting of: R², —D—R⁵ or


12. A compound of claim 1 wherein: (Z—W)_(t) or (Z—W)_(v) together withX¹ forms a 5 or 6 membered ring, said ring being a carbocycle,optionally substituted with 1 to 3 groups of R^(a); A is a double bond;Y is O; in the case where (Z—W)_(t) is used v is 0 or 1; in the casewhere (Z—W)_(v) is used t is 0 or 1; and all other variables aredescribed as above.
 13. A compound of claim 1 wherein R¹ is H or C₁₋₁₅alkyl; X¹ and X² are independently H, or halo; B is a 5 memberedheterocycle, wherein the combination of B and the aromatic ring to whichB is fused is benzofuran, the heterocycle being optionally unsubstitutedor substituted with 1 to 3 R^(a) groups; A is a double bond; Y is O orS; Y¹ is O; W is —CR⁶R⁷—; R^(a) is a member selected from the groupconsisting of: halo, aryl, heteroaryl, CF₃, OCF₃, CN, NO₂, R^(3′),OR^(3′); SR^(3′), S(O)R^(3′), SO₂R^(3′), NR^(3′)COR^(3′), COR^(3′),CON(R^(3′))₂, and SO₂N(R^(3′))₂, wherein said heteroaryl is selectedfrom the group consisting of tetrazole, benzothiophene, and benzofuran,said aryl and heteroaryl optionally substituted with 1 to 3 halo or C1-6alkyl groups; R^(3′) represents H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, aryl or heteroaryl, wherein said heteroaryl is selected fromthe group consisting of tetrazole, benzothiophene, and benzofuran; and Zis CO₂R^(3′), CONHSO₂Me, CONH₂ or 5-(1H-tetrazole).
 14. A compound ofclaim 1 wherein: R¹ is H or C₁₋₁₅ alkyl; X¹ and X² are independently H,or halo; A is a double bond; R⁴ is selected from the group consistingof: R², —D—R⁵ or

Y is O or S; Y¹ is O; W is —CR⁶R⁷—; R^(a) is a member selected from thegroup consisting of: halo, aryl, heteroaryl, CF₃, OCF₃, CN, NO₂, R^(3′),OR^(3′); SR^(3′), S(O)R^(3′), SO₂R^(3′), NR^(3′)COR^(3′), COR^(3′),CON(R^(3′))₂, and SO₂N(R^(3′))₂, wherein said heteroaryl is selectedfrom the group consisting of tetrazole, benzothiophene, and benzofuran,said aryl and heteroaryl optionally substituted with 1 to 3 halo or C1-6alkyl groups; R^(3′) represents H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, aryl or heteroaryl, wherein said heteroaryl is selected fromthe group consisting of tetrazole, benzothiophene, and benzofuran; and Zis CO₂R^(3′), CONHSO₂Me, CONH₂ or 5-(1H-tetrazole).
 15. A compound ofclaim 1 wherein: R¹ is C₁₋₁₅ alkyl; R⁴ is —D—R⁵ or

X² is H, or halo; A is a double bond; Y is O or S; Y¹ is O; R^(a) is amember selected from the group consisting of: halo, aryl, heteroaryl,CF₃, OCF₃, CN, NO₂, R^(3′), OR^(3′); SR^(3′), S(O)R^(3′), SO₂R^(3′),NR^(3′)COR^(3′), COR^(3′), CON(R^(3′))₂, and SO₂N(R^(3′))₂, wherein saidheteroaryl is selected from the group consisting of tetrazole,benzothiophene, and benzofuran, said aryl and heteroaryl optionallysubstituted with 1 to 3 halo or C1-6 alkyl groups; R^(3′) represents H,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl or heteroaryl, wherein saidheteroaryl is selected from the group consisting of tetrazole,benzothiophene, and benzofuran, (Z—W)_(t) or (Z—W)_(v) together with X¹forms a 5 or 6 membered ring, said ring being a carbocycle, optionallysubstituted with 1 to 3 groups of R^(a); in the case where (Z—W)_(t) isused v is 0 or 1; in the case where (Z—W)_(v) is used t is 0 or 1; andall other variables are as described above.
 16. A compound according toclaim 1 represented by one of the following structural formulas:

or a salt, ester or hydrate thereof.
 17. A compound in accordance withclaim 1 selected from the group consisting of:2-(2-(3-Phenyl-7-propylbenzofuran-6-yloxy)ethyl)benzothiophen-5-aceticacid;2-(2-(3-Neopentyl-7-propylbenzofuran-6-yloxy)ethyl)benzofuran-5-aceticacid; 2-(2-(4-Phenoxy-2-propylphenoxy)ethyl)benzofuran-5-acetic acid;2-(2-(3-Phenyl-7-propylbenzofuran-6-yloxy)ethyl)-benzofuran-5-aceticacid;2-(2-(4-Phenoxy-2-propylphenoxy)ethyl-4,5,6,7-tetrahydronaphtho[2,1-b]furan-7-carboxylicacid; or a salt or hydrate thereof.
 18. A compound according to claim 17which is:2-(2-(4-Phenoxy-2-propylphenoxy)ethyl)-4,5,6,7-tetrahydronaphtho[2,1-b]furan-7-carboxylicacid or a salt or hydrate thereof.
 19. A pharmaceutical compositionwhich is comprised of a compound as described in claim 2 in combinationwith a carrier.
 20. A pharmaceutical composition which comprises aninert carrier and a compound of claim
 1. 21. A pharmaceuticalcomposition in accordance with claim 19 which is further comprised of atleast one member selected from the group consisting of: a sulfonylurea,fibrate, HMG-CoA reductase inhibitor, beta-sitosterol inhibitor,cholesterol acyltransferase inhibitor, biguanide, cholestyramine,angiotensin II antagonist, melinamide, nicotinic acid, fibrinogenreceptor antagonist, aspirin, α-glucosidase inhibitor, insulinsecretagogue and insulin.
 22. A pharmaceutical composition whichcomprises an inert carrier and a compound of claim 1, in combinationwith a sulfonylurea, fibrate, HMG-CoA reductase inhibitor,beta-sitosterol inhibitor, cholesterol acyltransferase inhibitor,biguanide, cholestyramine, angiotensin II antagonist, melinamide,nicotinic acid, fibrinogen receptor antagonist, aspirin, α-glucosidaseinhibitor, insulin secretagogue or insulin.
 23. A pharmaceuticalcomposition which comprises an inert carrier and a compound of claim 1,in combination with fenfluramine, dexfenfluramine, phentermine or a β₃adrenergic receptor agonist.